Cycloalkylidene compounds as modulators of estrogen receptor

ABSTRACT

The present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel substituted cyclic alkylidene compounds that are particularly useful for selective estrogen receptor modulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed as a continuation application of U.S. Ser. No.10/565,296 filed on Feb. 15, 2007 which was filed pursuant to 35 U.S.C.§ 371 as a United States National Phase Application of InternationalApplication No. PCT/US2004/024308 filed Jul. 27, 2004, which claimspriority from U.S. 60/490,588 filed Jul. 28, 2003.

FIELD OF THE INVENTION

The present invention relates to novel compounds with a variety oftherapeutic uses, more particularly novel substituted cycloalkylidenecompounds that are particularly useful for selective estrogen receptormodulation.

BACKGROUND OF THE INVENTION

Estrogens are well-known endocrine regulators in the cellular processesinvolved in the development and maintenance of the reproductive system.Estrogens have also been shown to have important effects in manynon-reproductive tissues such as bone, liver, the cardiovascular system,and the central nervous system. The most widely accepted hypothesis ofhow estrogens exert their effects is by binding to an intracellularsteroid hormone receptor. After the receptor and bound ligand aretransferred to the nucleus of the cell, the complex binds to recognitionsites in DNA, which allows for the modulation of certain genes.Additionally, it is now becoming apparent that estrogens may mediatetheir effects via membrane-initiated signaling cascade, though much ofthis work is still experimental. Kousteni et al., Journal of ClinicalInvestigation, (2003), 111, 1651-1664, herein incorporated by referencewith regard to such teaching.

Certain substances have demonstrated the ability to exhibit theirbiological activity in a “tissue-selective” manner. In other words,tissue selectivity allows functionality as estrogen agonists in certaintissues, while acting as estrogen antagonists in other tissues. The term“selective estrogen receptor modulators” (SERMs) has been given to thesemolecules. Examples of SERMs include tamoxifen, raloxifene,lasofoxifene, clomiphene, and nafoxidine. The molecular basis for thistissue-selective activity is not completely understood. Without beinglimited to any particular theory, the ability of the ligand to place theestrogen receptor into different conformational states and allowing fordifferential capabilities in recruiting coactivator and corepressorproteins, as well as other important proteins involved intranscriptional regulation, is believed to play a role. See, McDonnell,D. P., The Molecular Pharmacology of SERMs, Trends Endocrinol. Metab.1999, 301-311, herein incorporated by reference with regard to suchdescription.

Historically estrogens were believed to manifest their biologicalactivity through a single estrogen receptor, now termed estrogenreceptor alpha (ERα). More recently, however, there was the discovery ofsecond subtype of estrogen receptor, termed estrogen receptor beta(ERβ). See, Kuiper et al., WO 97/09348 and Kuiper et al., Cloning of aNovel Estrogen Receptor Expressed in Rat Prostate and Ovary, Proc. Natl.Acad. Sci. U.S.A., 1996, pp. 5925-5930, herein incorporated by referencewith regard to such subtype. ERβ is expressed in humans. See, Mosselmanet al., ERβ: Identification and Characterization of a Novel HumanEstrogen Receptor, FEBR S Lett., 1996, pp. 49-53, herein incorporated byreference with regard to such expression. The discovery of this secondsubtype of estrogen receptor significantly increased the biologicalcomplexity of estrogen signaling and may be responsible for some of thetissue-selective actions of the currently available SERMs.

As noted above, estrogens have important effects in manynon-reproductive tissues. Thus, estrogen modulation is believed usefulin the treatment or prophylaxis of diseases and conditions associatedwith such tissues, including bone, liver, and the central nervoussystem. For example, osteoporosis is characterized by the net loss ofbone mass per unit volume. Such bone loss results in a failure of theskeleton to provide adequate structural support for the body, therebycreating an increased risk of fracture. One of the most common types ofosteoporosis is postmenopausal osteoporosis, which is associated withaccelerated bone loss subsequent to cessation of menses and declininglevels of endogenous estrogen in women. There is an inverse relationshipbetween densitometric measures of bone mass and fracture risk, for peri-and postmenopausal women in the process of rapid bone loss due todeclining levels of estrogen. See, Slemenda, et al., Predictors of BoneMass in Perimenopausal Women, A Prospective Study of Clinical Data UsingPhoton Abr sorptiometry, Ann. Intern. Med., 1990, pp. 96-101 andMarshall, et al., Meta-Analysis of How Well Measures of Bone MineralDensity Predict Occurrence of Osteoporotic Fractures, Br Med. J., 1996,pp. 1254-1259, each of which is herein incorporated by reference withregard to such relationship. Elderly women currently have a lifetimerisk of fractures of about 75%. In addition there is an approximate 40%risk of hip fracture for Caucasian women over age 50 in the UnitedStates. The economic burden from osteoporotic fractures is considerablebecause of the necessity of hospitalization. In addition, althoughosteoporosis is generally not thought of as life-threatening, themortality within 4 months of hip fracture is currently approximately 20to 30%. Current therapies for postmenopausal osteoporosis includehormone replacement therapy or treatment with other antiresorptiveagents such as bisphosphonates or calcitonin. Similarly, SERMS have beenshown to be effective in the treatment of postmenopausal osteoporosis(see, Lindsay, R.: Sex steroids in the pathogenesis and prevention ofosteoporosis. In: Osteoporosis 1988. Etiology, Diagnosis and Management.Riggs B L (ed)l, Raven Press, New York, USA (1988):333-358; BarzelUS:Estrogens in the prevention and treatment of postmenopausalosteoporosis:a review. Am J. Med (1988) 85:847-850; and Ettinger, B.,Black, D. M., et al., Reduction of Vertebral Fracture Risk inPostmenopausal Women with Osteoporosis Treated with Raloxifene, JAMA,1999, 282, 637-645, each of which is incorporated by reference withregard to such teaching).

As another example, the effects of estrogens on breast tissue,particularly breast cancer, have been well documented. For example, apreviously identified SERM, tamoxifen, decreases the risk of recurrentbreast cancer, contralateral breast cancer, and mortality as well asincreases the disease-free survival rate of patients with breast cancerat multiple stages of the disease. See, Cosman, F., Lindsay, R.Selective Estrogen Receptor Modulators: Clinical Spectrum, EndocrineRev., 1999, pp. 418-434, herein incorporated by reference with regard tosuch teaching. The profile of tamoxifen, however, is not ideal due topotential interactive properties on reproductive tissues, such asuterine tissues. There is room for an improved therapy for the treatmentof such cancers, namely a SERM with no agonist properties on anyreproductive tissues.

Cardiovascular disease is the leading cause of death amongpostmenopausal women. Until recently, the preponderance of datasuggested that estrogen replacement therapy in postmenopausal womenreduced the risk of cardiovascular disease, although some studiesreported no beneficial effect on overall mortality. See, Barrett-Connor,E. et al., The Potential of SERMs for Reducing the Risk of CoronaryHeart Disease, Trends Endocrinol. Metab., 1999, pp. 320-325, hereinincorporated by reference. The mechanism(s) by which estrogens werebelieved to exert their beneficial effects on the cardiovascular systemare not entirely clear. Potentially estrogen's effects on serumcholesterol and lipoproteins, antioxidant properties, vascular smoothmuscle proliferation, and inhibition of arterial cholesterolaccumulation were believed to play a role. Id. See also, Cosman, F.,Lindsay, R. Selective Estrogen Receptor Modulators: Clinical Spectrum,Endocrine Rev., 1999, pp. 418-434, herein incorporated by reference. Inlight of the recent reports of the HERS II and WHI studies, however,continuous combined Hormone Therapy, namely, CEE+MPA [Conjugated EquineEstrogen+Medroxy Progesterone Acetate], confers no cardiovascularbenefit in menopausal women. See, Hulley S., Grady, D., Bush, T., etal., Randomized trial of estrogen plus progestin for secondaryprevention of coronary heart disease in postmenopausal women. Heart andEstrogen/progestin Replacement Study (HERS) Research Group. J. Am. Med.Assoc. (1998) 280:605-613 and Wassertheil-Smoller S., Hendrix, S. L.,Limacher, M., et al., for the WHI Investigators. Effect of estrogen plusprogestin on stroke in postmenopausal women: the Women's HealthInitiative: a randomized trial. JAMA (2003) 289, 2673-2684, each hereinincorporated by reference with regard to such teaching). To what extentthese findings may be extrapolated to SERMs is an issue that remains tobe determined.

Other therapeutic alternatives include estrogen replacement therapyand/or hormone replacement therapy, which may be useful in the treatmentof vasomotor symptoms, genitourinary atrophy, depression, and diabetes.Over 75% of women experience vasomotor symptoms during the climactericyears. Clinical signs, such as vasomotor symptoms and genitourinaryatrophy, abate upon treatment with estrogen replacement therapy.Sagraves, R., J. Clin. Pharmacol. (1995), 35(9 Suppl):2S-10S, hereinincorporated by reference with regard to such teaching. Preliminary datasuggest that estradiol may alleviate depression during perimenopause andthat the combination of estrogens and selective serotonin reuptakeinhibitors may alleviate depression during the postmenopausal period.Soares, C. N., Poitras, J. R., and Prouty, J., Drugs Aging, (2003),20(2), 85-100, herein incorporated by reference with regard to suchteaching. Furthermore, hormone replacement therapy may improve glycemiccontrol among women with diabetes. Palin, S. L. et al., DiabetesResearch and Clinical Practice, (2001), 54, 67-77; Ferrara, A. et al.,Diabetes Care, (2001), 24(7), 1144-1150), each incorporated herein byreference with regard to such teaching. There is a need, however, forimproved therapies that present better side effect profiles.

The present inventors discovered a novel group of cycloalkylidenecompounds, which bind to and modulate estrogen receptor alpha andestrogen receptor beta. As SERMS, these compounds are believed to beuseful for the treatment and/or prophylaxis of menopausal orpostmenopausal disorders, —vasomotor symptoms, urogenital or vulvarvaginal atrophy, atrophic vaginitis, female sexual dysfunction, breastcancer, depressive symptoms, diabetes, bone demineralization, and thetreatment and/or prevention of osteoporosis.

SUMMARY OF THE INVENTION

The present invention includes novel compounds. The present inventionincludes compounds of formula (I):

including salts, solvates, and pharmacologically functional derivativesthereof wherein

-   R¹ is OH;-   each of R² and R⁴ independently are selected from OH, alkyl, or    halogen;-   each of p and q independently are selected from 0, 1, or 2;-   R³ is —(Y)_(z)—R⁸;-   z is 0 or 1;-   Y is —C≡C— or —CR^(e)═CR^(f)—;-   X is —(CH₂)_(n)— where n is 0, 1, 2, or 3, —C(R^(g))₂—, —O—, or —S—;-   each R⁵ is H; or-   both R⁵s together combine to form a bridging alkylene chain    —(CH₂)_(m)—, where m is 2, 3, or 4, when each R⁶ and each R⁷ is H    and X is —(CH₂)_(m-2)—;-   each of R⁶ and R⁷ are selected from H or alkyl; or-   X is —(CH₂)_(m)—, both R⁶s are H, and both R⁷s together combine to    form a bridging alkylene chain —(CH₂)_(m)—, where each m is the same    and is as defined; or-   X is —(CH₂)_(m)—, both R⁷s are H, and both R⁶s together combine to    form a bridging alkylene chain —(CH₂)_(m)—, where each m is the same    and is as defined;-   when z is 0, then R⁸ is alkyl, halogen, alkoxy, aryl, heteroaryl,    heterocyclyl, cyano, —O(R^(h))_(t)CN, —CO₂H, —(R^(h))_(t)CO₂H,    —O(R^(h))_(t)CO₂H, —(R^(h))_(t)OH, —O(R^(h))_(t)OH,    —O(R^(h))_(t)O(R^(h))_(t)OH, —CONR^(a)R^(b), —SO₂R^(d),    —NR^(a)SO₂R^(d), —COR^(c), or —NR^(a)COR^(c);-   when z is 1, then R⁸ is —CO₂H, —(R^(h))_(t)CO₂H, —(R^(h))_(t)OH,    —CONR^(a)R^(b), or —PO₃HR^(a); or-   when z is 1, and Y is —C≡C—, then R⁸ may also be H;-   t is 1 to 8;-   R^(a) is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;-   R^(b) is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;-   R^(c) is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;-   R^(d) is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or-   R^(a) and R^(b), R^(a) and R^(c), or R^(a) and R^(d) may combine    with the atoms to which they are bound to form a heteroaryl or    heterocyclyl ring; and-   R^(e) and R^(f) each are independently selected from H, alkyl,    halogen, and haloalkyl;-   R^(g) is alkyl;-   each R^(h) independently is —CR^(j)R^(k)—, where each of R^(j) and    R^(k) independently are selected from H and alkyl;-   wherein each occurrence of alkyl, cycloalkyl, aryl, heteroaryl, and    heterocyclyl may be optionally substituted.

Preferably The compound of claim 1 wherein alkyl is C₁₋₈alkyl, alkoxy isC₁₋₈alkoxy, alkenyl is C₂₋₈alkenyl, and alkynyl is C₂₋₈alkynyl.

In one embodiment, R¹ is substituted para on the depicted ring.

In one embodiment, p and q each are 0.

In one embodiment, z is 1, Y is —CR^(e)═CR^(f)—, and R⁸ is —CO₂H.Preferably R^(e) and R^(f) are H or C₁₋₈alkyl.

In one embodiment, z is 1, Y is —CR^(e)═CR^(f)—, and R⁸ is—C(O)NR^(a)R^(b). Preferably R^(a) and R^(b) each are H.

In one embodiment, z is 1, Y is —C≡C—, and R⁸ is —CO₂H,—(R^(h))_(t)CO₂H, or —(CH₂)_(t)OH.

In one embodiment each of R⁶ and R⁷ are H or C₁₋₈alkyl.

In one embodiment, X is —(CH₂)_(n)—. Preferably n is 1. Preferably R⁶and R⁷ are alkyl. In another embodiment preferably n is 2 or 3 andpreferably R⁶ and R⁷ are hydrogen.

In one embodiment X is —O—. Preferably R⁶ and R⁷ are alkyl.

In one embodiment, z is 0 and R⁸ is —CO₂H, —NR^(a)SO₂R^(d), aryl, orheteroaryl. In one embodiment R⁸ is aryl. Preferably aryl is phenyl,optionally substituted with one or more of cyano, halogen, heterocyclyl,—CO₂H, —(R^(h))_(t)OH, —SO₂R^(d), —C(O)NR^(a)R^(b), —NR^(a)COR^(c),—NR^(a)SO₂R^(d), and —CH═CH—CO₂H. Preferably R^(a) is H, R^(b) is H,R^(c) is alkyl, and R^(d) is alkyl. In another embodiment R⁸ is —CO₂H.In another embodiment R⁸ is —NR^(a)SO₂R^(d), R^(a) is H, and R^(d) isalkyl or aryl. In another embodiment R⁸ is isooxazolyl, oxazolyl,pyrimidyl, pyridyl, or furyl. In one embodiment R⁸ is —CONR^(a)R^(b),and R^(a) and R^(b) combine to form a 5 or 6 membered heterocyclyl ringoptionally substituted with —CO₂H.

Particularly preferred compounds of the present invention include:

-   (2E)-3-{4-[Cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenamide;-   (2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenamide;-   (2E)-3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenamide;-   4-[[4-(1H-Pyrrol-2-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   (2E)-3-{4-[(4,4-Dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[cyclohexylidene(4-hydroxy-3-methylphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{-4-[(4-Hydroxyphenyl)(tetrahydro-4H-thiopyran-4-ylidene)methyl]phenyl}-2-propenoic    acid;-   1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)-3-piperidinecarboxylic    acid;-   1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)-4-piperidinecarboxylic    acid;-   1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)proline;-   (2E)-3-{4-[bicyclo[3.3.1]non-9-ylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoic    acid;-   (2E)-3-{4-[Cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoic    acid;-   (2E)-3-{4-[(4-Hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoic    acid;-   N-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide;-   (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoic    acid;-   4-[[4-({2-[(2-Hydroxyethyl)oxy]ethyl}oxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   Ethyl hydrogen    (E)-2-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}ethenylphosphonate;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-2-methylphenyl}-2-propenoic    acid;-   (2E)-3-{3-Chloro-4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-3-fluorophenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(3-fluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoic    acid;-   4-[[4-(Methylsulfonyl)phenyl](3,3,5,5    tetramethylcyclohexylidene)methyl]phenol;-   4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzamide;-   4-[{4-[(2-Hydroxyethyl)oxy]phenyl}(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylcarboxylic    acid;-   4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenylcarboxylic    acid;-   (2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(cyclohexylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(2-fluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(4-hydroxy-2,3-dimethylphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cyclohexylidene(2,3-difluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic    acid;-   4-[[4-(3-hydroxy-1-propyn-1-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4-[(4-Ethynylphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoic    acid;-   {4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetic    acid;-   4-[Cycloheptylidene(4-hydroxyphenyl)methyl]benzoic acid;-   4-[Cyclohexylidene(4-hydroxyphenyl)methyl]benzoic acid;-   4-[Cyclooctylidene(4-hydroxyphenyl)methyl]benzoic acid;-   4-[[4-(1,3-Oxazol-2-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylcarboxamide;-   4-[[4-(5-Pyrimidinyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4-[[4′-(Methylsulfonyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   (2E)-3-{4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylyl}-2-propenoic    acid;-   4-[[4-(3-Pyridinyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol    trifluoroacetate;-   3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoic    acid;-   4-[(4,4-Dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoic    acid;-   4-[Cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoic    acid;-   3-{4-[Cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl}-acrylic    acid;-   N-{4-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide;-   N-{4-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-benzenesulfonamide;-   (2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoic    acid;-   ({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetic acid;-   (2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoic    acid;-   (2E)-3-{4-[Cycloheptylidene    (3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoic acid;-   4-{cycloheptylidene[4-(3-furanyl)phenyl]methyl}phenol;-   4-{Cycloheptylidene[4-(2-furanyl)phenyl]methyl}phenol;-   4-{cyclooctylidene[4-(2-furanyl)phenyl]methyl}phenol;-   4-{Cyclooctylidene[4-(3-furanyl)phenyl]methyl}phenol;-   4-{cyclooctylidene[4-(3,5-dimethyl-4-isoxazolyl)phenyl]methyl}phenol;-   4-{cycloheptylidene[4-(3,5-dimethyl-4-isoxazolyl)phenyl]methyl}phenol;-   4-[cycloheptylidene(4-hydroxyphenyl)methyl]benzonitrile;-   4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile;-   (2E)-3-{4-[(4-Hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoic    acid;-   (2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoic    acid;-   ({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetonitrile;-   4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoic    acid;-   ({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic    acid;-   4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic    acid;-   4-(Cycloheptylidene{4-[(2-hydroxyethyl)oxy]phenyl}methyl)phenol;-   2-({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoic    acid;-   2-({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl    phenyl}oxy)-2-methylpropanoic acid;-   ({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile;-   4-(Cycloheptylidene{4-[(2-hydroxy-1,1-dimethylethyl)oxy]phenyl}methyl)phenol;-   4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   ({4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic    acid;-   4-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic    acid;-   ({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile;-   4-[[4-(3-Hydroxypropyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   N-{4′-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-biphenyl-4-yl}-acetamide;-   N-{4′-[(4-Hydroxy-phenyl)-(3,3,5-5-tetramethyl-cyclohexylidene)-methyl]-biphenyl-4-yl}-methanesulfonamide;-   4-[[4-(3-furanyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4-[[4-(3,5-dimethyl-4-isoxazolyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4-[[4′-(4-morpholinyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   3-fluoro-4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenylcarbonitrile;-   4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenyl    carbonitrile;-   4′-[cyclooctylidene(4-hydroxyphenyl)methyl]-4-biphenylcarbonitrile;-   4-{Cycloheptylidene[4-(5-hydroxy-1-pentyn-1-yl)phenyl]methyl}phenol;-   4-[[4-(3-hydroxy-3-methyl-1-butyn-1-yl)phenyl](3,3,5,5-tetramethyl    cyclohexylidene)methyl]phenol;-   4-[[4-(4-hydroxy-1-butyn-1-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   5-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoic    acid;-   1-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}ethanone;-   4-[[4′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4-[[3′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;-   4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylic    acid; and-   4-[[2′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol;    including salts, solvates, and pharmacologically functional    derivatives thereof.

The present invention includes:

including salts, solvates, and pharmacologically functional derivativesthereof.

Another aspect of the present invention includes compounds substantiallyas hereinbefore defined with reference to any one of the Examples.

Another aspect of the present invention includes pharmaceuticalcompositions comprising the compounds and a pharmaceutically acceptablecarrier.

Another aspect of the present invention includes the compounds for useas an active therapeutic substance.

Another aspect of the present invention includes the compounds for usein the treatment or prophylaxis of conditions or disorders affected byselective estrogen receptor modulation. Preferably the treatment orprophylaxis relates to osteoporosis, bone demineralization, reduced bonemass, density, or growth, osteoarthritis, acceleration of bone fracturerepair and healing, acceleration of healing in joint replacement,periodontal disease, acceleration of tooth repair or growth, Paget'sdisease, osteochondrodysplasias, muscle wasting, the maintenance andenhancement of muscle strength and function, frailty or age-relatedfunctional decline (“ARFD”), sarcopenia, chronic fatigue syndrome,chronic myaligia, acute fatigue syndrome, acceleration of wound healing,maintenance of sensory function, chronic liver disease, AIDS,weightlessness, burn and trauma recovery, thrombocytopenia, short bowelsyndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn'sdisease and ulcerative colitis, obesity, eating disorders includinganorexia associated with cachexia or aging, hypercortisolism andCushing's syndrome, cardiovascular disease or cardiac dysfunction,congestive heart failure, high blood pressure, breast cancer, malignanttumore cells containing the androgen receptor including breast, brain,skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas,endometrium, lung, colon, and prostate, prostatic hyperplasia,hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity,adenomas and neoplasis of the prostate, hyperinsulinemia, insulinresistance, diabetes, syndrome X, dyslipidemia, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,depressive symptoms, nervousness, irritability, stress, reduced mentalenergy and low self-esteem, improvement of cognitive function,endometriosis, polycystic ovary syndrome, counteracting preeclampsia,premenstral syndrome, contraception, uterine fibroid disease, and/oraortic smooth muscle cell proliferation, vaginal dryness, pruritis,dyspareunia, dysuria, frequent urination, urinary tract infections,hypercholesterolemia, hyperlipidemia, peripheral vascular disease,restenosis, vasospasm, vascular wall damage due to immune responses,Alzheimer's disease, bone disease, aging, inflammation, rheumatoidarthritis, respiratory disease, emphysema, reperfusion injury, viralhepatitis, tuberculosis, psoriasis, systemic lupus erythematosus,amyotrophic lateral sclerosis, stroke, CNS trauma, dementia,neurodegeneration, breast pain and dysmenorrhea, menopausal orpostmenopausal disorders, vasomotor symptoms, urogenital or vulvarvaginal atrophy, atrophic vaginitis, female sexual dysfunction, forenhancing libido, for the treatment of hypoactive sexual disorder,sexual arousal disorder, for increasing the frequency and intensity oforgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatichypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto'sthyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, orreperfusion damage of ischemic myocardium. More preferably the treatmentor prophylaxis relates to menopausal or postmenopausal disorders,vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophicvaginitis, endometriosis, female sexual dysfunction, breast cancer,depressive symptoms, diabetes, bone demineralization, or osteoporosis.

Another aspect of the present invention includes the use of thecompounds in the manufacture of a medicament for use in the treatment orprophylaxis of conditions or disorders associated with selectiveestrogen receptor modulation. Preferably the medicament is for use inthe treatment or prophylaxis of osteoporosis, bone demineralization,reduced bone mass, density, or growth, osteoarthritis, acceleration ofbone fracture repair and healing, acceleration of healing in jointreplacement, periodontal disease, acceleration of tooth repair orgrowth, Paget's disease, osteochondrodysplasias, muscle wasting, themaintenance and enhancement of muscle strength and function, frailty orage-related functional decline (“ARFD”), sarcopenia, chronic fatiguesyndrome, chronic myaligia, acute fatigue syndrome, acceleration ofwound healing, maintenance of sensory function, chronic liver disease,AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, shortbowel syndrome, irritable bowel syndrome, inflammatory bowel disease,Crohn's disease and ulcerative colitis, obesity, eating disordersincluding anorexia associated with cachexia or aging, hypercortisolismand Cushing's syndrome, cardiovascular disease or cardiac dysfunction,congestive heart failure, high blood pressure, breast cancer, malignanttumore cells containing the androgen receptor including breast, brain,skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas,endometrium, lung, colon, and prostate, prostatic hyperplasia,hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity,adenomas and neoplasis of the prostate, hyperinsulinemia, insulinresistance, diabetes, syndrome X, dyslipidemia, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,depressive symptoms, nervousness, irritability, stress, reduced mentalenergy and low self-esteem, improvement of cognitive function,endometriosis, polycystic ovary syndrome, counteracting preeclampsia,premenstral syndrome, contraception, uterine fibroid disease, and/oraortic smooth muscle cell proliferation, vaginal dryness, pruritis,dyspareunia, dysuria, frequent urination, urinary tract infections,hypercholesterolemia, hyperlipidemia, peripheral vascular disease,restenosis, vasospasm, vascular wall damage due to immune responses,Alzheimer's disease, bone disease, aging, inflammation, rheumatoidarthritis, respiratory disease, emphysema, reperfusion injury, viralhepatitis, tuberculosis, psoriasis, systemic lupus erythematosus,amyotrophic lateral sclerosis, stroke, CNS trauma, dementia,neurodegeneration, breast pain and dysmenorrhea, menopausal orpostmenopausal disorders, vasomotor symptoms, urogenital or vulvarvaginal atrophy, atrophic vaginitis, female sexual dysfunction, forenhancing libido, for the treatment of hypoactive sexual disorder,sexual arousal disorder, for increasing the frequency and intensity oforgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatichypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto'sthyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, orreperfusion damage of ischemic myocardium. More preferably the conditionor disorder is menopausal or postmenopausal disorders, vasomotorsymptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis,endometriosis, female sexual dysfunction, breast cancer, depressivesymptoms, diabetes, bone demineralization, or osteoporosis.

Another aspect of the present invention includes a method for thetreatment or prophylaxis of conditions or disorders associated withselective estrogen receptor modulation comprising the administration ofthe compounds. Preferably the treatment or prophylaxis relates toosteoporosis, bone demineralization, reduced bone mass, density, orgrowth, osteoarthritis, acceleration of bone fracture repair andhealing, acceleration of healing in joint replacement, periodontaldisease, acceleration of tooth repair or growth, Paget's disease,osteochondrodysplasias, muscle wasting, the maintenance and enhancementof muscle strength and function, frailty or age-related functionaldecline (“ARFD”), sarcopenia, chronic fatigue syndrome, chronicmyaligia, acute fatigue syndrome, acceleration of wound healing,maintenance of sensory function, chronic liver disease, AIDS,weightlessness, burn and trauma recovery, thrombocytopenia, short bowelsyndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn'sdisease and ulcerative colitis, obesity, eating disorders includinganorexia associated with cachexia or aging, hypercortisolism andCushing's syndrome, cardiovascular disease or cardiac dysfunction,congestive heart failure, high blood pressure, breast cancer, malignanttumore cells containing the androgen receptor including breast, brain,skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas,endometrium, lung, colon, and prostate, prostatic hyperplasia,hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity,adenomas and neoplasis of the prostate, hyperinsulinemia, insulinresistance, diabetes, syndrome X, dyslipidemia, urinary incontinence,artherosclerosis, libido enhancement, sexual dysfunction, depression,depressive symptoms, nervousness, irritability, stress, reduced mentalenergy and low self-esteem, improvement of cognitive function,endometriosis, polycystic ovary syndrome, counteracting preeclampsia,premenstral syndrome, contraception, uterine fibroid disease, and/oraortic smooth muscle cell proliferation, vaginal dryness, pruritis,dyspareunia, dysuria, frequent urination, urinary tract infections,hypercholesterolemia, hyperlipidemia, peripheral vascular disease,restenosis, vasospasm, vascular wall damage due to immune responses,Alzheimer's disease, bone disease, aging, inflammation, rheumatoidarthritis, respiratory disease, emphysema, reperfusion injury, viralhepatitis, tuberculosis, psoriasis, systemic lupus erythematosus,amyotrophic lateral sclerosis, stroke, CNS trauma, dementia,neurodegeneration, breast pain and dysmenorrhea, menopausal orpostmenopausal disorders, vasomotor symptoms, urogenital or vulvarvaginal atrophy, atrophic vaginitis, female sexual dysfunction, forenhancing libido, for the treatment of hypoactive sexual disorder,sexual arousal disorder, for increasing the frequency and intensity oforgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatichypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto'sthyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, orreperfusion damage of ischemic myocardium. More preferably the conditionor disorder is menopausal or postmenopausal disorders, vasomotorsymptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis,endometriosis, female sexual dysfunction, breast cancer, depressivesymptoms, diabetes, bone demineralization, or osteoporosis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is described in terms known and appreciated bythose skilled in the art. For ease of reference certain terms hereafterare defined. The fact that certain terms are defined, however, shouldnot be considered as indicative that any term that is undefined isindefinite. Rather, all terms used herein are believed to describe theinvention in terms such that one of ordinary skill can appreciate thescope of the present invention.

As used herein the term “alkyl” refers to a straight or branched chainhydrocarbon, preferably having from one to twelve carbon atoms. Examplesof “alkyl” as used herein include, but are not limited to, methyl,ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl,n-pentyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, n-propylene, n-butylene, and the like.

As used herein the term “halogen” refers to fluorine, chlorine, bromine,or iodine.

As used herein the term “haloalkyl” refers to an alkyl group, as definedherein, which is substituted with at least one halogen. Examples ofbranched or straight chained “haloalkyl” groups useful in the presentinvention include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, and t-butyl substituted independently with one ormore halogens, for example, fluoro, chloro, bromo, and iodo. The term“haloalkyl” should be interpreted to include such substituents asperfluoroalkyl groups and the like.

As used herein the term “alkoxy” refers to the group —OR, where R isalkyl as defined above.

As used herein the term “acyl” refers to the group —C(O)R, where R isalkyl, aryl, heteroaryl, or heterocyclyl, as each is defined herein.

As used herein the term “hydroxy” refers to the group —OH.

As used herein the term “carboxy” refers to the group —C(O)OH.

As used herein the term “nitro” refers to the group —NO₂.

As used herein the term “amino” refers to the group —NH₂, or whenreferred to as substituted amino defines such groups substituted withalkyl.

As used herein, the term “cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring, preferably having from three to ten carbon atoms.Exemplary “cycloalkyl” groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

As used herein, the term “aryl” refers to a benzene ring or to a benzenering system fused to one or more additional benzene rings to form, forexample, anthracene, phenanthrene, or naphthalene ring systems. Examplesof “aryl” groups include, but are not limited to, phenyl, 2-naphthyl,1-naphthyl, biphenyl, and the like.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides arepermissible heteroatom substitutions. Examples of “heteroaryl” groupsused herein include, but should not be limited to, furan, thiophene,pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine,pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, indazole, and the like.

As used herein, the term “heterocycle” or “heterocyclyl” refers to amono- or poly-cyclic ring system containing optionally one or moredegrees of unsaturation and also containing one or more heteroatoms.Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfuroxides, and dioxides. Preferably the ring is three to ten-membered andis either saturated or has one or more degrees of unsaturation. Suchrings may be optionally fused to one or more of another “heterocyclic”ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).Examples of “heterocyclic” groups include, but are not limited to,tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

As used herein throughout the present specification, the phrase“optionally substituted” or variations thereof denote an optionalsubstitution, including multiple degrees of substitution, with one ormore substituent group. The phrase should not be interpreted so as to beimprecise or duplicative of substitution patterns herein described ordepicted specifically. Rather, those of ordinary skill in the art willappreciate that the phrase is included to provide for obviousmodifications, which are encompassed within the scope of the appendedclaims.

Exemplary optional substituent groups include acyl; alkyl; alkenyl;alkynyl; alkylsulfonyl; alkoxy; cyano; halogen; haloalkyl; hydroxy;nitro; cycloalkyl, which may be further substituted with acyl, alkoxy,alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl,hydroxy, or nitro; heterocyclyl, which may be further substituted withacyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro; aryl, which may be further substitutedwith acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano,halogen, haloalkyl, hydroxy, or nitro; heteroaryl, which may be furthersubstituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl,cyano, halogen, haloalkyl, hydroxy, or nitro; —CO₂H; —(R^(h))_(t)OH;—CONR^(a)R^(b); —NR^(a)SO₂R^(d); —NR^(a)COR^(c); —SO₂NR^(a)R^(b);—SO₂NR^(a)COR^(c); and —CONR^(a)SO₂R^(d), where each of R^(a), R^(b),R^(c), and R^(d) independently are as herein defined.

The compounds of formulas (I) may crystallize in more than one form, acharacteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of formula (I). Polymorphismgenerally can occur as a response to changes in temperature, pressure,or both. Polymorphism can also result from variations in thecrystallization process. Polymorphs can be distinguished by variousphysical characteristics known in the art such as x-ray diffractionpatterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also includedwithin the scope of the invention are the individual isomers of thecompounds represented by formula (I), as well as any wholly or partiallyequilibrated mixtures thereof. The present invention also includes theindividual isomers of the compounds represented by the formulas above asmixtures with isomers thereof in which one or more chiral centers areinverted.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts. Representative salts include acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, monopotassium maleate, mucate, napsylate, nitrate,N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate, triethiodide, trimethylammonium, and valerate salts. Othersalts, which are not pharmaceutically acceptable, may be useful in thepreparation of compounds of this invention and these should beconsidered to form a further aspect of the invention.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I, or a salt or physiologically functional derivative thereof)and a solvent. Such solvents, for the purpose of the invention, shouldnot interfere with the biological activity of the solute. Non-limitingexamples of suitable solvents include, but are not limited to water,methanol, ethanol, and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Non-limiting examples of suitablepharmaceutically acceptable solvents include water, ethanol, and aceticacid. Most preferably the solvent used is water.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention that, upon administration to a mammal, is capable ofproviding (directly or indirectly) a compound of the present inventionor an active metabolite thereof. Such derivatives, for example, estersand amides, will be clear to those skilled in the art, without undueexperimentation. Reference may be made to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. The term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

For use in therapy, therapeutically effective amounts of a compound offormula (I), as well as salts, solvates, and physiological functionalderivatives thereof, may be administered as the raw chemical.Additionally, the active ingredient may be presented as a pharmaceuticalcomposition. Accordingly, the invention further provides pharmaceuticalcompositions that include effective amounts of compounds of the formula(I) and salts, solvates, and physiological functional derivativesthereof, and one or more pharmaceutically acceptable carriers, diluents,or excipients. The compounds of formula (I) and salts, solvates, andphysiologically functional derivatives thereof, are as described above.The carrier(s), diluent(s) or excipient(s) must be acceptable, in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient of the pharmaceutical composition.In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a compound of the formula (I) or salts, solvates, andphysiological functional derivatives thereof, with one or morepharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, the age andweight of the animal, the precise condition requiring treatment and itsseverity, the nature of the formulation, and the route of administrationare all factors to be considered. The therapeutically effective amountultimately should be at the discretion of the attendant physician orveterinarian. For example, an effective amount of a compound of formula(I) for the treatment of humans suffering from osteoporosis, generally,should be in the range of 0.1 to 100 mg/kg body weight of recipient(mammal) per day. More usually the effective amount should be in therange of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adultmammal the actual amount per day would usually be from 70 to 700 mg.This amount may be given in a single dose per day or in a number (suchas two, three, four, five, or more) of sub-doses per day such that thetotal daily dose is the same. An effective amount of a salt, solvate, orphysiologically functional derivative thereof, may be determined as aproportion of the effective amount of the compound of formula (I) perse. Similar dosages should be appropriate for treatment of the otherconditions referred to herein that are mediated by estrogen.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the formula (I), depending on the condition being treated,the route of administration, and the age, weight, and condition of thepatient. Preferred unit dosage formulations are those containing a dailydose or sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient. Such pharmaceutical formulations maybe prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants useful in these dosage forms include, for example,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum, and the like. Tablets are formulated, for example, by preparing apowder mixture, granulating or slugging, adding a lubricant anddisintegrant, and pressing into tablets. A powder mixture may beprepared by mixing the compound, suitably comminuted, with a diluent orbase as described above. Optional ingredients include binders, such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants, such as paraffin, resorption accelerators such as aquaternary salt and/or abr sorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and salts, solvates, and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

The compounds of formula (I) and salts, solvates, and physiologicallyfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone (PVP), pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986), incorporated herein by reference as related to such deliverysystems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base. Pharmaceuticalformulations adapted for topical administrations to the eye include eyedrops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent. Pharmaceuticalformulations adapted for topical administration in the mouth includelozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring agents.

The compounds of the present invention and their salts, solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theconditions herein described. For example, in osteoporosis therapy,combination with other osteoporosis therapeutic agents is envisaged.Osteoporosis combination therapies according to the present inventionthus comprise the administration of at least one compound of formula (I)or a salt, solvate, or physiologically functional derivative thereof,and the use of at least one other osteoporosis treatment method.Preferably, combination therapies according to the present inventioncomprise the administration of at least one compound of formula (I) or asalt, solvate, or physiologically functional derivative thereof, and atleast one other osteoporosis treatment agent, for example, a bonebuilding agent. The compound(s) of formula (I) and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately, administration may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. Theadministration in combination of a compound of formula (I) salts,solvates, or physiologically functional derivatives thereof with otherosteoporosis treatment agents may be in combination by administrationconcomitantly in: (1) a unitary pharmaceutical composition includingeach compound; or (2) separate pharmaceutical compositions eachincluding one of the compounds. Alternatively, the combination may beadministered separately in a sequential manner wherein one treatmentagent is administered first and the other(s) subsequently or vice versa.Such sequential administration may be close in time or remote in time.

The compounds of the present invention and their salts, solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theconditions herein described. For example, regarding the use of thecompounds of the present invention in the prevention of reduced bonemass, density, or growth, combination may be had with other anabolic orosteoporosis therapeutic agents. As one example, osteoporosiscombination therapies according to the present invention would thuscomprise the administration of at least one compound of the presentinvention or a salt, solvate, or physiologically functional derivativethereof, and the use of at least one other osteoporosis therapy. As afurther example, combination therapies according to the presentinvention include the administration of at least one compound of thepresent invention or a salt, solvate, or physiologically functionalderivative thereof, and at least one other osteoporosis treatment agent,for example, an anti-bone resorption agent. The compound(s) of thepresent invention and the other pharmaceutically active agent(s) may beadministered together or separately and, when administered separately,administration may occur simultaneously or sequentially, in any order.The amounts of the compound(s) and the agent(s) and the relative timingsof administration will be selected in order to achieve the desiredcombined therapeutic effect. The administration in combination of acompound of the present invention including salts, solvates, orphysiologically functional derivatives thereof with other treatmentagents may be in combination by administration concomitantly in: (1) aunitary pharmaceutical composition including both compounds; or (2)separate pharmaceutical compositions each including one of thecompounds. Alternatively, the combination may be administered separatelyin a sequential manner wherein one treatment agent is administered firstand the other second or vice versa. Such sequential administration maybe close in time or remote in time.

As noted, one potential additional osteoporosis treatment agent is abone building (anabolic) agent. Bone building agents can lead toincreases in parameters such as bone mineral density that are greaterthan those than can be achieved with anti-resorptive agents. In somecases, such anabolic agents can increase trabecular connectivity leadingto greater structural integrity of the bone.

Other potential therapeutic combinations include the compounds of thepresent invention combined with other compounds of the presentinvention, growth promoting agents, growth hormone secretagogues, growthhormone releasing factor and its analogs, growth hormone and itsanalogs, somatomedins, alpha-ardenergic agonists, serotonin 5-HT_(D)agonists, selective serotonin reuptake inhibitors, agents that inhibitsomatostatin or its release, 5-α-reductase inhibitors, aromataseinhibitors, GnRH inhibitors, parathyroid hormone, bisphosphonates,estrogen, testosterone, SERMs, progesterone receptor agonists, and/orwith other modulators of nuclear hormone receptors.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions and, as such, the compounds of thepresent invention may be used in combination with a variety of othersuitable therapeutic agents useful in the treatment or prophylaxis ofthose disorders or conditions. Non-limiting examples includecombinations of the present invention with anti-diabetic agents,anti-osteoporosis agents, anti-obesity agents, anti-inflammatory agents,anti-anxiety agents, anti-depressants, anti-hypertensive agents,anti-platelet agents, anti-thrombotic and thrombolytic agents, cardiacglycosides, cholesterol or lipid lowering agents, mineralocorticoidreceptor antagonists, phosphodiesterase inhibitors, kinase inhibitors,thyroid mimetics, anabolic agents, viral therapies, cognitive disordertherapies, sleeping disorder therapies, sexual dysfunction therapies,contraceptives, cytotoxic agents, radiation therapy, anti-proliferativeagents, and anti-tumor agents. Additionally, the compounds of thepresent invention may be combined with nutritional supplements such asamino acids, triglycerides, vitamins, minerals, creatine, piloic acid,carnitine, or coenzyme Q10.

An aspect of the present invention is the use of the compounds of thepresent invention for the treatment or prophylaxis of a variety ofdisorders including, but not limited to, osteoporosis, bonedemineralization and/or the prevention of reduced bone mass, density, orgrowth, osteoarthritis, acceleration of bone fracture repair andhealing, acceleration of healing in joint replacement, periodontaldisease, acceleration of tooth repair or growth, Paget's disease,osteochondrodysplasias, muscle wasting, the maintenance and enhancementof muscle strength and function, frailty or age-related functionaldecline (“ARFD”), sarcopenia, chronic fatigue syndrome, chronic myalgia,acute fatigue syndrome, acceleration of wound healing, maintenance ofsensory function, chronic liver disease, AIDS, weightlessness, burn andtrauma recovery, thrombocytopenia, short bowel syndrome, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and ulcerativecolitis, obesity, eating disorders including anorexia associated withcachexia or aging, hypercortisolism and Cushing's syndrome,cardiovascular disease or cardiac dysfunction, congestive heart failure,high blood pressure, breast cancer, malignant tumore cells containingthe androgen receptor including breast, brain, skin, ovary, bladder,lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon,and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis ofthe prostate, hyperinsulinemia, insulin resistance, diabetes, syndromeX, dyslipidemia, urinary incontinence, artherosclerosis, libidoenhancement, sexual dysfunction, depression, depressive symptoms,nervousness, irritability, stress, reduced mental energy and lowself-esteem, improvement of cognitive function, endometriosis,polycystic ovary syndrome, counteracting preeclampsia, premenstralsyndrome, contraception, uterine fibroid disease, and/or aortic smoothmuscle cell proliferation, vaginal dryness, pruritis, dyspareunia,dysuria, frequent urination, urinary tract infections,hypercholesterolemia, hyperlipidemia, peripheral vascular disease,restenosis, vasospasm, vascular wall damage due to immune responses,Alzheimer's disease, bone disease, aging, inflammation, rheumatoidarthritis, respiratory disease, emphysema, reperfusion injury, viralhepatitis, tuberculosis, psoriasis, amyotrophic lateral sclerosis,stroke, CNS trauma, dementia, neurodegeneration, breast pain,dysmenorrhea, menopausal or postmenopausal disorders, vasomotorsymptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis,female sexual dysfunction, for enhancing libido, for the treatment ofhypoactive sexual disorder, sexual arousal disorder, for increasing thefrequency and intensity of orgasms, vaginismus, osteopenia,endometriosis, BPH (benign prostatic hypertrophy), autoimmune diseases,Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myastheniagravis, reperfusion damage of ischemic myocardium,

In particular, the compounds of the present invention are believeduseful, either alone or in combination with other agents, in thetreatment of menopausal or postmenopausal disorders, vasomotor symptoms,urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexualdysfunction, breast cancer, depressive symptoms, diabetes, bonedemineralization, and the treatment and/or prevention of osteoporosis.

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working Examples.

In all of the examples described below, protecting groups for sensitiveor reactive groups are employed where necessary in accordance withgeneral principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers and includes not only racemic compounds butthe individual enantiomers as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as are known in the art. Resolution ofthe final product, an intermediate, or a starting material may beeffected by any suitable method known in the art. See, for example,Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L.N. Mander (Wiley-Interscience, 1994), incorporated by reference withregard to stereochemistry.

Experimental Section

Abbreviations:

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, thefollowing abbreviations may be used in the examples and throughout thespecification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); psi (pounds per square inch); M (molar); mM (millimolar);Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (roomtemperature); h (hours); d (days); EI (electron impact); min (minutes);TLC (thin layer chromatography); mp (melting point); RP (reverse phase);T_(r) (retention time); TFA (trifluoroacetic acid); TEA (triethylamine);THF (tetrahydrofuran); TFAA (trifluoroacetic anhydride); CD₃OD(deuterated methanol); CDCl₃ (deuterated chloroform); DMSO(dimethylsulfoxide); SiO₂ (silica); atm (atmosphere); EtOAc (EtOAc);CHCl₃ (chloroform); HCl (hydrochloric acid); Ac (acetyl); DMF(N,N-dimethylformamide); Me (methyl); Cs₂CO₃ (cesium carbonate); EtOH(ethanol); Et (ethyl); tBu (tert-butyl); MeOH (methanol); CH₂Cl₂(dichloromethane); MgSO₄ (magnesium sulfate); CH₃CN (acetonitrile);K₂CO₃ (potassium carbonate); TiCl₄ (titanium tetrachloride); EtOAc(EtOAc); CO₂ (carbon dioxide); Pd(OAc)₂ (palladium acetate); Et₂O(diethyl ether); P(o-tolyl)₃ (tri-o-tolylphosphine); Na₂SO₄ (sodiumsulfate); NaH (sodium hydride); DME (1,2-dimethoxyethane); NaI (sodiumiodide); NaOH (sodium hydroxide); NH₄Cl (ammonium chloride); NaHCO₃(sodium bicarbonate); AlCl₃ (aluminum chloride); (C₂H₅O)₂P(O)H (diethylphosphite); NaN₃ (sodium azide); CBr₄ (carbon tetrabromide); PPh(triphenylphosphine); CuI (copper (I) iodide); Pd(Ph₃P)₄(tetrakis(triphenylphosphine)palladium (0)); (iPrO)₃B (triisopropylborate); nBuLi (butyllithium); Na₂CO₃ (sodium carbonate); DMAP(4-(dimethylamino)pyridine); eq (equivalents); HRMS (high resolutionmass spectrometry); LCMS (liquid chromatography mass spectrometry); LRMS(low resolution mass spectrometry); APCI (Atmospheric Pressure ChemicalIonization); LiHMDS (lithium bis(trimethylsilyl)amide); Pd(Ph₃P)₂Cl₂(dichlorobis(triphenylphosphine)palladium(II)); EDC(N-(3-dimethylaminopropyl)-N′-ethyl-carbodimide; dpppe(1,5-bis(diphenylphosphanyl)pentane; DMAc (N,N-dimethylacetamide); HPLC(high performance liquid chromatography); tmeda(N,N,N′,N′,-tetramethylethylenediamine); Pd₂(dba)₃(dipalladiumtris(dibenzylidene acetone)).

Unless otherwise noted, reagents and solvents were obtained fromcommercial suppliers and were used without further purification. Unlessotherwise indicated, all reactions were conducted at room temperatureand all temperatures are expressed in ° C. (degrees Centigrade).

Thin-layer chromatography (TLC) was performed on silica gel 60 F₂₅₄precoated plates. Detection was effected by exposure to UV light (254nm). Flash and flush column chromatography was performed using SilicaGel 60. Reverse phase preparative and analytical HPLC were performedusing C18 columns and acetonitrile:water gradients with 0.05% TFA as amodifier.

Compound purity and characterization were determined by ¹H-NMR, liquidchromatography-mass spectrometry (LCMS), high resolution massspectrometry (HRMS), combustion (elemental) analysis, HPLC, and meltingpoint. Compounds of general formula I were typically found to havepurities of >90%.

¹H NMR spectra were recorded on Varian INOVA-300 and Varian INOVA-400instruments. Chemical shifts are expressed in parts per million (ppm, δunits). Coupling constants are in units of hertz (Hz). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), dd (doublet of doublet), t (triplet), q(quartet), m (multiplet), or br (broad).

Low resolution mass spectra were obtained on Micromass ZQ, MicromassZMD, Micromass QuattroMicro, and Micromass GCT instruments fromMicromass Ltd., Altricham, UK, using either Atmospheric PressureChemical Ionization (APCI) or ESI Ionization (ESI).

High resolution mass spectral data (HRMS) were recorded with MicromassLCT and Micromass GCT instruments.

Combustion analyses were performed by Atlantic Microlab, Inc. (Norcross,Ga.).

Melting points were recorded in open capillary tubes and areuncorrected.

The bolded numerals reference the compounds as depicted in the followingschemes. For the following schemes, depending on subsequent chemistryand functional group compatibility, the phenol groups of specificintermediates may need to be protected using synthetic methodsappreciated by those skilled in the art.

Scheme 1 General Route to Substituted Cycloalkylidene Diphenylethylenes

The substituted symmetric alkylidene compound VI can be prepared inthree steps as described in Scheme 1. Friedel-Crafts acylation betweenacid chloride I and anisole II provides benzophenone III. ForFriedel-Crafts reaction conditions, see Friedel-Crafts and RelatedReactions, G. A. Olah, ed., Vol 3, Pt 1, pp 1-382, J. Wiley and Sons,New York (1964); G. A. Olah, Friedel-Crafts Chemistry, WileyInterscience, New York, (1973); and Larock, R. C., Comprehensive OrganicTransformations, VCH Publishers, New York, 1989, each hereinincorporated by reference with regard to such teaching. Deprotection ofIII with aluminum chloride in refluxing benzene gives benzophenone (IV).McMurry coupling between benzophenone IV and ketone V provides thecycloalkylidene diphenylethylene VI. For McMurry reaction conditions,see Mukaiyama et al., Chem. Lett. (1973), 1041; Lenoir, Synthesis,(1977), 553; Lenoir and Burghard, J. Chem. Res. (S) (1980), 396;McMurry, Chem. Rev. (1989), 89, 1513-1524; McMurry, Acc. Chem. Res.(1983) 16, 405-511; and S. Gauthier et al., J. Org. Chem., (1996), 61,3890-3893, each herein incorporated by reference with regard to suchteaching. Ketone V is either commercially available or may be preparedby synthetic methods appreciated by those skilled in the art.

Further elaboration of the R3 substituent of VI can be carried out. Forexample, when R3 is an ester, saponification will yield the carboxylicacid VII and treatment with a reducing agent such as LAH yields thecorresponding alcohol VIII. Acid VII can also be converted to acarboxamide IX. Treatment of acid (VII) with an amine in the presence ofa coupling agent such as EDC and DMAP in dichloromethane provides amideIX. Alternatively, acid VII can be converted to the acid chloride usingoxalyl chloride and DMF in toluene followed by treatment of the crudeacid chloride with an amine to give amide IX. For conversion ofcarboxylic acids to amides, see Larock, R. C., Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

Similarly, preparation of analogues of compounds VI-IX from abenzophenone related to compound III in which the methoxy group is metato the carbonyl group can be accomplished using identical procedures(See Example 68).

Scheme 2 General Route to Cycloalkylidene Diphenylethylene Acrylic Acidsand Acrylamides

Acrylic acid XI can be prepared in two steps from compound VI asillustrated in Scheme 2. Heck coupling of VI with an acrylate ester(wherein R is a suitable alkyl group (e.g. methyl, ethyl, tert-butyl)provides X. For reviews of the Heck reaction, see Heck, Acc. Chem. Res.(1979), 12, 146-151; Heck, Pure Appl. Chem. (1978), 50, 691-701; R. F.Heck, Palladium Reagents in Organic Syntheses, Academic Press, New York(1985), 179-321, Bender, Stakem, and Heck, J. Org. Chem. (1982),47,1278; Spencer, J. Organomet. Chem. (1983), 258, 101; and Brase,Stefan; De Meijere, Armin. Palladium-catalyzed Coupling of OrganylHalides to Alkenes—the Heck Reaction, Metal-Catalyzed Cross-CouplingReactions (1998), 99-166, Publisher: Wiley-VCH Verlag GmbH, Weinheim,Germany, each herein incorporated by reference with regard to suchteaching. Ester hydrolysis of X provides acrylic acid XI.

An analogue of XI wherein the phenolic hydroxyl group is replaced byhydrogen (i.e. R¹ is H as herein described) may be prepared according tothe methods described in Schemes 1 and 2 by employing commerciallyavailable (4-bromophenyl)(phenyl)methanone.

An analogue of XI wherein the phenolic hydroxyl group is replaced byfluorine (i.e. R¹ is F as herein described) can be prepared by themethods described in Schemes 1 and 2 by employing(4-bromophenyl)(4-fluorophenyl)methanone which can be prepared bymethods described in the literature (for example, Z. Vejdelek et al.,Collect. Czech. Chem. Commun., (1984), 49(11), 2649-2660, hereinincorporated by reference with regard to such teaching).

Alternative routes to preparing acrylic acid compounds illustrated by XIin Scheme 2 are described in Examples 28 and 29 below.

Acrylic acid XI can be converted to an amide as illustrated in Scheme 2.Treatment of acrylic acid (XI) with an amine in the presence of acoupling agent such as EDC and DMAP in dichloromethane provides amideXII. Alternatively, acrylic acid XI can be converted to the acidchloride using oxalyl chloride and DMF in toluene followed by treatmentof the crude acid chloride with an amine to give amide XII. Forconversion of carboxylic acids to amides, see Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

Scheme 3 General Route to Cycloalkylidene Diphenylethylenes from ArylHalide VI

Cycloalkylidene VI is a versatile intermediate that can be used toprepare a variety of compounds as described in Scheme 3.

Coupling of VI with an aryl or heteroaryl-substituted boronic acid usingSuzuki reaction conditions provides XIII. For reaction conditions of theSuzuki coupling reaction, see, Miyaura, N., Suzuki, A. Chem. Rev. 1995,95, 2457-2483; Suzuki, A., J. Organometallic Chem. (1999), 576, 147-168;and Suzuki, A. in Metal-catalyzed Cross-coupling Reactions, Diederich,F., and Stang, P. J., Eds.; Wiley-VCH: New York, (1998), pp. 49-97, eachherein incorporated by reference with regard to such teaching.Alternatively, XIII can be prepared by Suzuki-coupling of boronic acidXV with an aryl or heteroaryl halide. Boronic acid XV can be prepared bymetal-halogen exchange of VI using butyllithium followed by treatment ofthe resulting organolithium with triisopropyl borate and subsequenthydrolysis. For reaction conditions, see X. Deng et al., J. Org. Chem.,(2002), 67(15), 5279-5283 and P. J. Hajduk et al., J. Amer. Chem. Soc.,(1997), 119(25), 5818-5827, each herein incorporated by reference.

Metal-halogen exchange of VI using butyl lithium followed by treatmentwith carbon dioxide or DMF provides benzoic acid XVI and benzaldehydeXVII respectively. For reaction conditions, see T. Mizuno et al.,Tetrahedron, (1999), 55(31), 9455-9468; J. W. Lampe et al., J. Med.Chem., (2002), 45(12), 2624-2643; R. G. Leenders et al., Bioorg. Med.Chem. (1999), 7(8), 1597-1610; and A. Endo et al., J. Amer. Chem. Soc.,(2002), 124(23), 6552-6554, each herein incorporated by reference.

Amides can be prepared from XVI by methods illustrated and described inScheme 2. Benzaldehyde XVII can be converted to acrylate ester X viaWadsworth-Emmons chemistry (For Wadsworth-Emmons chemistry, see J.Boutagy and R. Thomas Chem. Rev. (1974), 74, 87-99; Wadsworth, Org.React (1977), 25, 73-253; Y. Momose, et al., J. Med. Chem., (2002),45(7), 1518-1534; and S. D. Bull et al., J. Chem. Soc. Perkin Trans I,(2001), 23, 3112-3121, each herein incorporated by reference with regardto such teaching.

Sonagashira coupling of VI with a propiolate ester, propiolate alcoholor (trimethylsilyl)acetylene provides aromatic alkyne XIV. See Campbell,I. B. “The Sonagashira Cu—Pd-catalyzed alkyne coupling reaction” inOrganocopper Reagents, Taylor, Richard J. K. ed., (1994), 217-35.Publisher: IRL Press, Oxford, UK; G. C. Nwokogu et al., J. Org. Chem.,(1994), 59(9), 2506-2510; and A. P. Kozikowski J. Med. Chem. (2000), 43(6), 1215-1222 and T. Eckert and J. Ipaktschi Synth. Commun. (1998), 28,327-336, each herein incorporated by reference with regard to suchteaching. Compound XIV can be further treated to prepare additional newanalogues. For example, when R=TMS, the TMS group can be removed toyield the corresponding terminal acetylene (R═H). When R=ester,hyrolysis or reduction affords the corresponding acid and alcoholrespectively (see conditions described in Scheme 1).

Scheme 4 General Synthesis of Cycloalkylidene Diphenylethylene Oxazole

The 2-substituted oxazole XVIII is prepared in two steps from benzoicacid XVI as described in Scheme 4. Treatment of XVI with oxalyl chloridegives acid chloride XIX which is then treated with 1H-1,2,3-triazole inthe presence of base to provide oxazole XVIII. For reaction conditionsleading to the formation of an oxazole from either an aromatic acidchloride or benzamide, see Murugesan, N. et al., J. Med. Chem. (2000),43, 3111-3117, herein incorporated by reference with regard to suchteaching.

Scheme 5 General Synthesis of Cycloalkylidene DiphenylethyleneSulfonamides and Amides

Nitroaniline XX can be converted to a sulfonamide (XXIV) or amide (XXV)as described in Scheme 5. Treatment of XX with a reducing agent such assodium dithionite provides aniline XXI. Acylation of XXI with a sulfonylchloride or an acid chloride provides sulfonamide XXII or carboxamideXXIII respectively. McMurry coupling of XXII or XXIII with ketone V asdescribed in Scheme 1 provides XXIV or XXV. Reductive alkylation of XXIby methods known to one skilled in the art gives aniline XXVI which canthen be treated as described above to give sulfonamide XXVII or amideXXVIII. Treatment of XXVII or XXVIII with ketone V yields sulfonamideXXIX or amide XXX.

Scheme 6 Synthesis of Oxyalkyl Substituted CycloalkylideneDiphenylethylenes

A variety of alkyl derivatives can be prepared in two or three steps viao-alkylation of phenol XXXI as illustrated in Scheme 6. As describedabove, compounds similar to XXXI can be prepared by McMurry couplingbetween an appropriately substituted benzophenone and ketone V. ForMcMurry reaction conditions, see references cited for Scheme 1 above.o-Alkylation of XXXI can be accomplished in the presence of a suitablebase and a haloester such as XXXII (wherein R is a suitable alkyl group,e.g. methyl, ethyl, tert-butyl). Saponification of the resulting esterXXXIII provides acid XXXIV. Conversion of ester XXXIII to the alcoholXXXV can be effected by treatment with a reducing agent such as lithiumaluminum hydride (LAH). Similarly, phenol XXXI can be alkylated with ahaloacetonitrile XXXVI or haloalcohol XXXVII to yield compounds XXXVIIIand XXXIX respectively. For examples of related phenol alkylationreactions see Rubin, V. et al., Bioorganic & Med. Chem. (2001), 9,1579-1586, herein incorporated by reference with regard to suchteaching.

EXAMPLES

The following specific examples are included as illustrations and arenot to be construed as limiting the scope of the present invention.

Example 1 (5)

Step 1: (4-Bromophenyl)[4-(methyloxy)phenyl]methanone (1)

To a cooled (ice bath, 5° C.) mixture of 4-bromobenzoyl chloride (25.0g, 0.114 mol) and anisole (15.5 g, 0.143 mol, 1.25 eq) in CH₂Cl₂ (500mL) was added AlCl₃ (19.0 g, 0.143 mol, 1.25 eq) portion-wise over aperiod of 20 minutes with stirring under a nitrogen atmosphere. Theresulting reaction mixture was allowed to stir between 5° C. and 20° C.for 3 h. The reaction mixture was poured slowly into 20% aqueous HCl(500 mL), stirred for 15 min, and layers were separated. The aqueouslayer was further extracted with CH₂Cl₂ (3×250 mL). The combined organiclayer washed with water (200 mL), brine (200 mL) dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford 33.48 g(100%) of compound 1 as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 3.91(s, 3 H), 6.99 (d, J=8.7 Hz, 2 H), 7.65 (s, 4 H), 7.82 (d, J=8.7 Hz, 2H).

Step 2: (4-Bromophenyl)(4-hydroxyphenyl)methanone (2)

To a stirred solution of (4-bromophenyl)[4-(methyloxy)phenyl]methanone(1) (27.0 g, 0.93 mol) in toluene (400 mL) was slowly added AlCl₃ (32.0g, 0.23 mol, 2.5 eq) via a powder addition funnel under a nitrogenatmosphere at RT. The stirred reaction mixture was heated at reflux for5 h under a blanket of N₂. The reaction mixture was allowed to cool toRT and then poured into 10% aqueous HCl (1 L). The reaction mixture wastransferred to a separatory funnel and the layers were separated. Theaqueous phase was extracted with EtOAc (4×250 mL). The combined organiclayer washed with brine (2×100 mL), dried (Na₂SO₄), and filtered. Thefiltrate was concentrated under reduced pressure to afford 25.75 g(100%) of compound 2 as a tan solid that was used in subsequentreactions without any further purification. ¹H NMR (300 MHz, DMSO-d₆): δ6.89 (d, J=8.7 Hz, 2 H), 7.60 (d, J=8.4 Hz, 2 H), 7.66 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.4 Hz, 2 H), 10.48 (s, 1 H).

Step 3: 4-[(4-Bromophenyl)(cyclopentylidene)methyl]phenol (3)

To a stirred suspension of zinc powder (0.71 g, 10.9 mmoL) in anhydrousTHF (15 mL) was slowly added, via syringe, TiCl₄ (0.58 mL, 1.0 g, 5.3mmoL) at RT under a nitrogen atmosphere. The stirred reaction mixturewas heated at reflux under a nitrogen atmosphere for 2.5 h. To therefluxing reaction mixture was added a solution of(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.408 g, 1.47 mmol) andcyclopentanone (0.38 mL, 0.36 g, 4.3 mmol) in THF (15 mL) and heatingcontinued an additional 2 h. The reaction mixture was allowed to cool toroom temperature and water (10 mL) slowly added. The reaction mixturewas then filtered through a pad of Celite and the Celite pad washed withEtOAc. The filtrate was transferred to a separatory funnel and theorganic layer was separated. The organic phase washed with brine, dried(MgSO₄), filtered, and the filtrate concentrated in vacuo to give thecrude product. The crude product was purified by flash chromatography onsilica gel with hexanes:EtOAc (100:0 to 60:40) to give 0.391 g (81%) ofcompound 3 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.59 (m,4 H), 2.27 (m, 4 H), 6.66 (d, J=8.5 Hz, 2 H), 6.89 (d, J=8.4 Hz, 2 H),7.04 (d, J=8.4 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H), 9.32 (s, 1 H). HRMS(EI) Calcd for C₁₈H₁₇BrO: 328.0463 (M⁺). Found: 328.0469.

Step 4:1,1-Dimethylethyl(2E)-3-{4-[cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(4)

4-[(4-Bromophenyl)(cyclopentylidene)methyl]phenol (3) (0.351 g, 1.07mmol), tert-butyl acrylate (0.94 mL, 0.82 g, 6.4 mmol, 6 eq), Pd(OAc)₂(0.051 g, 0.23 mmol, 0.21 eq), Et₃N (0.89 mL, 0.65 g, 6.4 mmol, 6 eq),P(o-tolyl)₃ (0.139 g, 0.46 mmol, 0.43 eq), and anhydrous CH₃CN (16 mL)were combined in a round-bottomed flask and the reaction mixture washeated overnight at 85° C., with stirring, under a nitrogen atmosphere.The reaction mixture was allowed to cool to room temperature andtransferred to a separatory funnel with the aid of EtOAc and water. Thelayers were separated and the organic phase washed with brine, driedover MgSO₄, filtered, and the filtrate was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel with hexanes:EtOAc (100:0 to 50:50) to give 0.30 g (74%) ofcompound 4 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.45 (s,9 H), 1.60 (m, 4 H), 2.30 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.67 (d,J=8.6 Hz, 2 H), 6.90 (d, J=8.4 Hz, 2 H), 7.12 (d, J=8.2 Hz, 2 H), 7.49(d, J=15.9 Hz, 1 H), 7.58 (d, J=8.3 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI)Calcd for C₂₅H₂₈O₃: 376.2038 (M⁺). Found: 376.2046.

Step 5:(2E)-3-{4-[Cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (5)

To an ice-water cooled solution of1,1-dimethylethyl(2E)-3-{4-[cyclopentylidiene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(4) (0.28 g, 0.74 mmol) in dichloromethane (5 mL) was slowly addedtrifluoroacetic acid (5 mL) with stirring under a nitrogen atmosphere.After 1 h, the reaction mixture was concentrated in vacuo to give asolid. The solid was dissolved in dichloromethane and the solution wasconcentrated in vacuo to give a pale tan solid. The solid was trituratedwith diethyl ether and filtered to give the acrylic acid as an off-whitesolid. The solid was dried overnight under vacuum at 70° C., however, ¹HNMR indicated that solvent remained in the sample. The solid wasdissolved in methanol and the solution was concentrated in vacuo to givean oil. The oil was dissolved in methanol and the solution wasconcentrated in vacuo under high vacuum at 60° C. to give an oil.Dichloromethane was added to the oil and crystallization was inducedwith the aid of a spatula. The suspension was filtered and the solid wasdried in a vacuum oven overnight at 70° C. to give 0.072 g (30%) ofcompound 5 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.60 (m, 4H), 2.30 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H), 6.67 (d, J=8.4 Hz, 2 H),6.90 (d, J=8.4 Hz, 2 H), 7.13 (d, J=8.2 Hz, 2 H), 7.53 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.3 Hz, 2 H), 9.32 (s, 1 H). The compound was silatedprior to EI analysis. HRMS (EI) Calcd for C₂₇H₃₆Si₂O₃: 464.2203 (M⁺).Found: 464.2210.

Example 2 (8)

Step 1: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]phenol (6)

To a 3-neck round-bottomed flask were added zinc powder (1.96 g, 30mmol) followed by anhydrous THF (40 mL). To the stirred suspension wasslowly added, via syringe, TiCl₄ (1.6 mL, 2.77 g, 14.6 mmol) at roomtemperature. The reaction mixture was heated at reflux with stirringunder a nitrogen atmosphere for 2 h. To the refluxing reaction mixturewas added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2)(1.1 g, 3.61 mmol) and cyclohexanone (1.1 mL, 1.04 g, 10.6 mmol) inanhydrous tetrahydrofuran (40 mL). The stirred reaction mixture washeated at reflux under a nitrogen atmosphere for 2 h. The oil bath wasremoved and the reaction mixture was allowed to cool to roomtemperature. To the reaction mixture was slowly added water (24 mL)followed by 10% aqueous K₂CO₃ (24 mL). The reaction mixture was filteredthrough a pad of Celite and the pad washed with EtOAc. The filtrate wastransferred to a separatory funnel with the aid of water and EtOAc andthe layers were separated. The organic phase washed with brine, driedover MgSO₄, filtered, and the filtrate was concentrated in vacuo to givethe crude product. The crude product was purified by flashchromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give1.17 g (95%) of compound 6 as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.52 (m, 6 H), 2.12 (m, 4 H), 6.65 (d, J=8.4 Hz, 2 H), 6.82(d, J=8.4 Hz, 2 H), 6.97 (d, J=8.3 Hz, 2 H), 7.44 (d, J=8.3 Hz, 2 H),9.32 (s, 1 H). HRMS (EI) Calcd for C₁₉H₁₉BrO: 342.0619 (M⁺). Found:342.0627.

Step 2:1,1-Dimethylethyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(7)

To a round-bottomed flask were added4-[(4-bromophenyl)(cyclohexylidene)methyl]phenol (6) (0.465 g, 1.35mmol), tert-butyl acrylate (0.58 mL, 0.508 g, 3.96 mmol, 2.9 eq),Pd(OAc)₂ (0.03 g, 0.134 mmol, 0.1 eq), triethylamine (0.54 mL, 0.39 g,3.87 mmol, 2.9 eq), P(o-tolyl)₃ (0.08 g, 0.26 mmol, 0.19 eq), and CH₃CN(6 mL). The reaction mixture was heated overnight at 75° C. withstirring under a nitrogen atmosphere. Thin layer chromatographyindicated the reaction was not complete. To the reaction mixture wereadded P(o-tolyl)₃ (0.087 g, 0.29 mmol, 0.21 eq), tert-butyl acrylate(0.58 mL, 0.51 g, 3.96 mmol, 2.9 eq), paladium II acetate (0.033 g,0.147 mmol), triethylamine (0.54 mL, 0.39 g, 3.87 mmol), and CH₃CN (2mL). The reaction mixture was heated at 75° C. with stirring under anitrogen atmosphere for three days. The reaction mixture was allowed tocool to room temperature and transferred to a separatory funnel with theaid of EtOAc and H₂O. The layers were separated and the organic phasewas washed with brine. The organic solution was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product asan oil. The crude product was purified by flash chromatography on silicagel with hexanes:EtOAc (100:0 to 50:50) to give 0.40 g (76%) of compound7 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.45 (s, 9 H),1.52 (m, 6 H), 2.14 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.66 (d, J=8.5Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.1 Hz, 2 H), 7.48 (d,J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.31 (s, 1 H). The sample wassilated prior to EI analysis. HRMS (EI) Calcd for C₂₉H₃₈O₃Si: 462.2590(M⁺). Found: 462.2592.

Step 3:(2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (8)

A solution of1,1-dimethylethyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(7) (0.24 g, 0.61 mmol) in CH₂Cl₂ (6 mL) was cooled in an ice-water bathand stirred under a nitrogen atmosphere. To the cold solution was slowlyadded trifluoroacetic acid (6 mL). The reaction mixture was stirred inthe ice-water bath under a nitrogen atmosphere for 1 h. The reactionmixture was concentrated to give the crude product as a solid. The crudeproduct was dissolved in CH₂Cl₂ and the solution was concentrated togive a solid. The crude product was transferred to a separatory funnelwith the aid of CH₂Cl₂ and H₂O. The organic phase was removed and theaqueous phase that contained suspended solids was extracted twice withCH₂Cl₂. The organic phase was removed and the aqueous suspension wasfiltered with the aid of H₂O. The filtered white solid was dissolved inCH₂Cl₂ and MeOH and the solution was filtered. The filtrate wasconcentrated and the resulting solid was dried in a vacuum oven to give135 mg (67%) of compound 8 as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.52 (m, 6 H), 2.15 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H), 6.66(d, J=8.4 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.0 Hz, 2 H),7.52 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.0 Hz, 2 H), 9.31 (s, 1 H), 12.31(br s, 1 H). The sample was silated prior to EI analysis. HRMS (EI)Calcd for C₂₈H₃₈O₃Si₂: 478.2360 (M⁺). Found: 478.2376.

Example 3 (11)

Step 1: 4-[(4-Bromophenyl)(cycloheptylidene)methyl]phenol (9)

To a three-neck round-bottomed flask equipped with a magnetic stir bar,reflux condenser, rubber septum, and two nitrogen inlets, was added zincpowder (13.0 g, 199 mmol) followed by anhydrous THF (200 mL). To thestirred suspension was slowly added TiCl₄ (11.0 mL, 19.0 g, 100.0 mmol)via syringe (caution: vigorous fuming). The reaction mixture was heatedat reflux for 2 h. To the refluxing reaction mixture was added asolution of cycloheptanone (9.0 mL, 8.56 g, 76.3 mmol) and(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (6.91 g, 24.9 mmol) in THF(200 mL) slowly via syringe. The reaction mixture was heated at refluxunder a nitrogen atmosphere with stirring for 2 h. The oil bath wasremoved and the reaction mixture was allowed to cool to roomtemperature. The three neck round-bottomed flask was equipped with anaddition funnel and water (150 mL) was slowly added to the reactionmixture followed by 10% aqueous K₂CO₃ (150 mL). The reaction mixture wasfiltered through a pad of Celite. The pad washed with EtOAc. Thefiltrate was transferred to a separatory funnel and the layers wereseparated. The organic phase washed with brine, dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product asan orange oil. The crude product was partially purified by flushchromatography on silica gel with hexanes:EtOAc (100:0 to 95:5) to givea solid. The solid was triturated with hexanes and filtered to give 6.3g (71%) of compound (9) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.50 (m, 8 H), 2.20 (m, 4 H), 6.66 (d, J=8.5 Hz, 2 H), 6.89(d, J=8.4 Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H),9.30 (s, 1 H).

Step 2:1,1-Dimethylethyl(2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(10)

To a round-bottomed flask were added4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (4.0 g, 11.2mmol), t-butyl acrylate (7.2 mL, 6.3 g, 49.2 mmol, 4.4 eq), Pd(OAc)₂(0.52 g, 2.3 mmol, 0.21 eq), Et₃N (9.5 mL, 6.90 g, 68.2 mmol, 6.1 eq),P(o-tolyl)₃ (1.3 g, 4.2 mmol, 0.38 eq), and CH₃CN (100 mL). The reactionmixture was heated overnight at 75° C. with stirring under a nitrogenatmosphere. The reaction mixture was allowed to cool to room temperatureand then transferred to a separatory funnel with the aid of EtOAc andH₂O. The layers were separated, and the organic phase washed with brine,dried (MgSO₄), filtered, and the filtrate was concentrated to give thecrude product as a red-orange oil. The crude product was purified byflush chromatography on silica gel with hexanes:EtOAc (9:1 to 4:1) togive 4.46 g (98%) of compound 10 as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.45 (s, 9 H), 1.50 (m, 8 H), 2.21 (m, 4 H), 6.42 (d, J=16.1Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.90 (d, J=8.4 Hz, 2 H), 7.10 (d,J=8.2 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.28(s, 1 H).

Step 3:(2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (11)

To an ice-water cooled mixture of1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(10) (4.42 g, 10.9 mmol) and CH₂Cl₂ (20 mL) was slowly addedtrifluoroacetic acid (10 mL) with stirring under a nitrogen atmosphere.After 3 h, the reaction mixture was filtered. The filtered solid waswashed with CH₂Cl₂ and dried to give 2.2 g of compound 11 as a whitesolid. The filtrate was concentrated and the impure product waspartially purified by flash chromatography on silica gel withCH₂Cl₂:MeOH (100:0 to 9:1) to give a yellow solid. The solid wastriturated with Et₂O and the suspension was filtered. The filtered solidwas dried to give a second crop of compound 11 (354 mg) as a pale tansolid. The Et₂O filtrate noted above was concentrated in vacuo and theimpure product was crystallized from hexanes and EtOAc. The solid wasdried to give a third crop of compound 11 (185 mg) as a pale tan solid.The total yield of 11 was 2.74 g (72%). Analytical data for all threebatches were comparable. The analytical data is herein presented for thefirst batch. ¹H NMR (400 MHz, DMSO-d₆): δ 1.50 (m, 8 H), 2.21 (m, 4 H),6.43 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.90 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.0 Hz, 2 H), 7.52 (d, J=16.1 Hz, 1 H), 7.57 (d, J=8.0Hz, 2 H), 9.28 (s, 1 H), 12.21 (br s, 1 H). LRMS (ESI): m/z 347 (M−H)⁻.Anal. Calcd for C₂₃H₂₄O₃: C, 79.28; H, 6.94. Found: C, 79.16; H, 6.97.

Example 4 (12)

Step 1:(2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenamide(12)

To a stirred solution of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.121 g, 0.63 mmol), 1-hydroxybenzotriazole hydrate(0.087 g, 0.644 mmol), 4-dimethylaminopyridine (0.012 g, 0.098 mmol),pyridine (5 mL), and ammonia (0.5 M in 1,4-dioxane) (1.4 mL, 0.7 mmol)was added a solution of(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (8) (174 mg, 0.52 mmol) in pyridine (5 mL). The reaction mixturewas stirred at room temperature under a nitrogen atmosphere for 4 d. Thereaction mixture was concentrated and the crude product was partitionedbetween H₂O and CH₂Cl₂. The organic phase was separated and washed with1 N HCl (aq.) followed by brine. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product.The crude product was purified by flash chromatography on silica gelwith CH₂Cl₂:MeOH (100:0 to 90:10) to give the desired product. The solidwas dried under vacuum at 70° C. to give 29 mg (17%) of compound 12 as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.54 (m, 6 H), 2.15 (m, 4 H),6.53 (d, J=15.8 Hz, 1 H), 6.67 (d, J=8.5 Hz, 2 H), 6.85 (d, J=8.4 Hz, 2H), 7.06 (m, 3 H), 7.36 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.2 Hz, 2 H),7.50 (br s, 1 H), 9.33 (s, 1). The compound was silated prior to EIanalysis. HRMS (EI) Calcd for C₂₅H_(31 N)O₂Si: 405.2124 (M⁺). Found:405.2126.

Example 5 (13)

Step 1:(2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenamide(13)

To a stirred suspension of(2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (11) (0.23 g, 0.66 mmol) in toluene (6 mL) was slowly added oxalylchloride (0.12 mL, 0.175 g, 1.38 mmol, 2.1 eq) followed by DMF (2-3drops) at room temperature under a nitrogen atmosphere. The reactionmixture was stirred for 0.25 h. Dichloromethane (6 mL) was added to thereaction mixture (to aid the dissolution of solids) and the reactionmixture was stirred at room temperature for 2 h. Oxalyl chloride (0.12mL, 0.175 g, 1.38 mmol, 2.1 eq) and DMF (2 drops) were added to thereaction mixture and stirring was continued for 3 h. The reactionmixture was concentrated in vacuo. Toluene was added to the crude acidchloride and the solvent was removed in vacuo. To the crude acidchloride were added ammonia (0.5 M in 1,4-dioxane) (6 mL, 3 mmol, 4.5eq) followed by CH₂Cl₂ (5 mL). The reaction mixture was stirredovernight at room temperature under a nitrogen atmosphere. The reactionmixture was transferred to a separatory funnel with the aid of CH₂Cl₂and the solution washed with water. The layers were separated and theorganic phase was dried over MgSO₄, filtered, and the filtrate wasconcentrated to give the crude amide as a gold-yellow oil. The crudeproduct was purified by flash chromatography on silica gel withCH₂Cl₂:MeOH (100:0 to 95:5) to give a solid which was dried at 70° C.under vacuum to give 0.058 g (25%) of compound 13 as a tan solid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.51 (m, 8 H), 2.22 (m, 4 H), 6.53 (d, J=15.9 Hz,1 H), 6.66 (d, J=8.5 Hz, 2 H), 6.91 (d, J=8.3 Hz, 2 H), 7.06 (br s, 1H), 7.12 (d, J=8.1 Hz, 2 H), 7.35 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.1Hz, 2 H), 7.50 (br s, 1 H), 9.29 (s, 1 H). HRMS (ESI) Calcd forC₂₃H₂₆NO₂: 348.1964 (M+H)⁺. Found: 348.1951.

Example 6 (16)

Step 1:4-[(4-Bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)

To a stirred suspension of zinc powder (23.4 g, 0.36 mol) in THF (300mL) was slowly added TiCl₄ (20 mL, 0.18 mol) via a syringe at roomtemperature under a nitrogen atmosphere. The reaction mixture was heatedat reflux for 1 h. A solution of(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (10.0 g, 0.036 mol) and3,3,5,5-tetramethylcyclohexanone (16.7 g, 0.108 mol) in THF (100 mL) wasadded to the reaction mixture. The reaction mixture was heated at refluxwith stirring under a nitrogen atmosphere for an additional 2 h. Thereaction mixture was allowed to cool to room temperature. To thereaction mixture was poured into a 10% aqueous K₂CO₃ (1 L). The reactionmixture was filtered through a pad of Celite and the pad washed withEtOAc. The filtrate was transferred to a separatory funnel and thelayers were separated. The aqueous phase was further extracted withEtOAc (4×250 mL). The combined organic phase washed with brine (2×10mL), dried (Na₂SO₄), filtered, and then filtrate was concentrated underreduced pressure to give the crude product as a gold-yellow oil. Thecrude product was purified by flash chromatography on silica gel withhexanes:EtOAc (100:0 to 1:1) as an eluent to afford 10.45 g (73%) ofcompound 14 as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.91 (s, 6 H),0.95 (s, 6H), 1.31 (s, 2 H), 1.96 (s, 2 H), 1.99 (s, 2 H), 4.67 (s, 1H),6.76 (d, J=8.7 Hz, 2 H), 7.03 (d, J=6.0 Hz, 2 H), 7.05 (d, J=6.0 Hz, 2H), 7.41 (d, J=8.4 Hz, 2 H). HRMS (EI) Calcd for C₂₃ H₂₇BrO: 398.1245(M⁺). Found: 398.1248.

Step 2:Ethyl(2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate(15)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(10.2 g, 0.0255 mol), ethyl acrylate (28 mL, 0.255 mol.),dichlorobis(triphenylphosphine) palladium (II) (0.895 g, 1.28 mmol, 5mol %), Et₃N (17.6 mL, 0.128 mol), and DMF (50 mL). The stirred reactionmixture was heated to 110° C. for 18 h under a nitrogen atmosphere. Thereaction mixture was allowed to cool to room temperature and thendiluted with Et₂O (200 mL). The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to give crude product.The crude reaction mixture in DMF was diluted with EtOAc (400 mL),washed with water (2×100 mL), brine (1×100 mL), dried (Na₂SO₄),filtered, and then concentrated under reduced pressure to afford thecrude product as an oil. The crude product was purified by flashchromatography on silica gel with hexanes:EtOAc (19:1 to 1:1) as aneluent to give 8.02 g (75%) of compound 15 as a pale yellow solid. ¹HNMR (300 MHz, CDCl₃): δ 0.88 (s, 6 H), 0.91 (s, 6 H), 1.31 (s, 2 H),1.35 (t, J=7.2 Hz, 3 H), 1.99 (s, 2 H), 2.00 (s, 2 H), 4.28 (q, J=7.2Hz, 2 H), 5.35 (broad s, 1H), 6.41 (d, J=16.2 Hz, 1 H), 6.77 (d, J=8.4Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.20 (d, J=8.10 Hz, 1 H), 7.44 (d,J=8.40 Hz, 2 H), 7.68 (d, J=16.2 Hz, 1H). HRMS (EI) Calcd for C₂₈H₃₄O₃:418.57 (M⁺). Found: 419.17. Note: Excess ethyl acrylate can be distilledfrom the reaction mixture before work-up.

Step 3:(2E)-3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoicacid (16)

To a stirred solution ofethyl(2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate(15) (7.75 g, 0.0185 mmol) in THF (100 mL) and EtOH (100 mL) was slowlyadded 1 N NaOH (93 mL) solution at RT. The reaction mixture was heatedto 70° C. and stirred at that temperature for 4.5 h. Reaction mixturewas cooled to room temperature and then poured into 20% aqueous HCl (350mL). The product was separated out as an off-white solid. The suspensionwas filtered and the filtered solid was dried to afford 6.01 g (83%) ofcompound 16 as an off-white solid. mp 219-220° C. ¹H NMR (300 MHz,DMSO-d₆): δ 0.89 (s, 6 H), 0.90 (s, 6 H), 1.27 (s, 2 H), 1.91 (s, 2 H),1.94 (s, 2 H), 6.47 (d, J=15.9 Hz, 1 H), 6.68 (d, J=8.1 Hz, 2 H), 6.95(d, J=8.4 Hz, 2 H), 7.16 (d, J=8.1 Hz, 2 H), 7.52 (d, J=15.9 Hz, 1 H),7.60 (d, J=8.1 Hz, 2 H), 9.31 (s, 1 H), 12.35 (s, 1H). LRMS (ESI): m/z389 (M−H)⁻.

Example 7 (17)

Step 1:(2E)-3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenamide(17)

To a stirred suspension of(2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoicacid (16) (0.18 g, 0.46 mmol) in CH₂Cl₂ (6 mL) at room temperature wasadded oxalyl chloride (0.15 mL, 0.218 g, 1.72 mmol, 3.7 eq) followed byseveral drops of DMF (Note: vigorous bubbling occurred upon addition ofDMF). The reaction mixture was stirred under a nitrogen atmosphere for 1h and concentrated in vacuo. Toluene was added to the crude acidchloride and the solvent was removed in vacuo. To the crude acidchloride was added ammonia (0.5 M in 1,4-dioxane) (6 mL) and the turbidreaction mixture stirred at room temperature under a nitrogen atmospherefor 3 h. Ammonia (0.5 M in 1,4-dioxane) (2 mL) was added to the reactionmixture and stirring was continued overnight at room temperature under anitrogen atmosphere. The reaction mixture was concentrated in vacuo.Ammonia (0.5 M in 1,4-dioxane) (8 mL) and CH₂Cl₂ (8 mL) were added tothe residue. The flask was equipped with a rubber septum and thereaction mixture was stirred at room temperature for 2 d. The reactionmixture was transferred to a separatory funnel and partitioned betweenCH₂Cl₂ and H₂O. The layers were separated and the aqueous phase wasextracted with CH₂Cl₂. The organic extracts were combined, washed withbrine, dried (MgSO₄) filtered, and the filtrate was concentrated to givethe crude product as an amorphous solid. The crude product was purifiedby flash chromatography on silica gel with CH₂Cl₂:MeOH (100:0 to 19:1)as eluant to provide the product which was dried to give 0.026 g (15%)of compound 17 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.87(s, 6 H), 0.88 (s, 6 H), 1.25 (s, 2 H), 1.89 (s, 2 H), 1.92 (s, 2 H),6.53 (d, J=15.8 Hz, 1 H), 6.66 (d, J=8.5 Hz, 2 H), 6.93 (d, J=8.5 Hz, 2H), 7.06 (br s, 1), 7.14 (d, J=8.1 Hz, 2 H), 7.35 (d, J=15.9 Hz, 1 H),7.45 (d, J=8.1 Hz, 2 H), 7.50 (br s, 1 H), 9.30 (s, 1). HRMS (ESI) Calcdfor C₂₆H_(32 N)O₂: 390.2433 (M+H)⁺. Found: 390.2427.

Example 8 (19)

Step 1: 1,1-Dimethylethyl2-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1H-pyrrole-1-carboxylate(18)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.127 g, 0.32 mmoL), 1-N-BOC-pyrrole-2-boronic acid (0.21 g, 1.0 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirredreaction mixture was heated at reflux overnight under a nitrogenatmosphere. The oil bath was removed and the reaction mixture wasallowed to cool at RT. The reaction mixture was transferred to aseparatory funnel and partitioned between H₂O and EtOAc. The organicphase was separated, dried over MgSO₄, filtered, and the filtrate wasconcentrated in vacuo to give an orange-brown oil. The crude product waspurified by flash chromatography on silica gel with a hexanes:EtOAcgradient (100:0 to 80:20) to give 111 mg (72%) of compound 18 as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.88 (s, 12 H), 1.24 (m,11 H), 1.92 (s, 2 H), 1.94 (s, 2 H), 6.19 (m, 1 H), 6.23 (m, 1 H), 6.65(d, J=8.5 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H), 7.09 (d, J=8.1 Hz, 2 H),7.21 (d, J=8.0 Hz, 2 H), 7.31 (m, 1 H), 9.27 (s, 1 H). LCMS (ESI): m/z508 (M+Na)⁺.

Step 2:4-[[4-(1H-Pyrrol-2-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(19)

To a stirred solution of 1,1-dimethylethyl2-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1H-pyrrole-1-carboxylate(18) (0.087 g, 0.18 mmoL) in anhydrous THF (1.8 mL) was added slowlysodium methoxide (0.5 M in MeOH) (1.4 mL, 0.7 mmoL) at RT under anitrogen atmosphere. The reaction mixture was allowed to stir at RTovernight. The reaction mixture was concentrated in vacuo and the crudeproduct was purified by reverse phase preparative HPLC on a C-18 columnwith a CH₃CN:H₂O gradient (75:25 to 100:0) and 0.05% TFA as a modifierto give 34 mg (49%) of compound 19 as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 0.87 (s, 6 H), 0.88 (s, 6 H), 1.25 (s, 2 H), 1.91 (s, 4H), 6.06 (m, 1 H), 6.42 (m, 1 H), 6.65 (d, J=8.5 Hz, 2 H), 6.78 (m, 1H), 6.93 (d, J=8.5 Hz, 2 H), 7.05 (d, J=8.0 Hz, 2 H), 7.49 (d, J=8.0 Hz,2 H), 9.25 (s, 1 H), 11.18 (s, 1 H). LCMS (ESI): m/z 386 (M+H)⁺.

Example 9 (22)

Step 1: 4,4-Dimethylcyclohexanone (20)

This compound was prepared according to the method described by H-J Liu,et al., (Can. J. Chem. (1988), 66, 2345) with modification. To athree-neck round-bottomed flask was added palladium on carbon (DegussaType, 10% wt. (dry basis)) (0.167 g). The flask was evacuated and thenfilled with nitrogen and the evacuation/fill cycle was repeated twicemore. To the flask was added a solution of4,4-dimethyl-2-cyclohexene-1-one (2.1 mL, 2.0 g, 16 mmol) in EtOAc (100mL). The flask was evacuated and then filled with nitrogen and theevacuation/fill cycle was repeated once more. The flask was evacuatedand then filled with hydrogen using a balloon. The reaction mixture wasstirred under a hydrogen atmosphere at room temperature overnight. Theflask was evacuated and filled with nitrogen. The reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc. Thefiltrate was concentrated to give 1.63 g (82%) of compound 20 as acolorless liquid that solidified to a white solid. ¹HNMR is consistentwith that reported in the cited reference. ¹H NMR (400 MHz, CDCl₃): δ1.08 (s, 6 H), 1.65 (t, J=6.9 Hz, 4 H), 2.33 (t, J=6.9 Hz, 4 H).

Step 2:1,1-Dimethylethyl(2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(21)

To a three-neck round-bottomed flask equipped with two nitrogen inlets,reflux condenser, rubber septum, and magnetic stir bar were added zincpowder (0.53 g, 8.1 mmol) and THF (15 mL). To the stirred suspension wasslowly added TiCl₄ via syringe at room temperature under a nitrogenatmosphere (Note: significant fuming occurred upon addition of TiCl₄).The reaction mixture was heated at reflux for 2 h. To the refluxingreaction mixture was added a solution of 4,4-dimethylcyclohexanone (20)(0.447 g, 3.54 mmol) and (4-bromophenyl)(4-hydroxyphenyl)methanone (2)(0.314 g, 1.13 mmol) in THF (15 mL). The reaction mixture was heated atreflux with stirring under a nitrogen atmosphere for 2 h. The reactionmixture was allowed to cool to room temperature. To the stirred reactionmixture was added water (8 mL) followed by 10% aqueous K₂CO₃ (8 mL). Themixture was filtered through a pad of Celite. The pad washed with EtOAc.The filtrate was transferred to a separatory funnel and washed withwater. The organic phase was separated, washed with brine, dried overMgSO₄, filtered, and the filtrate was concentrated to give a pale tansolid. The intermediate aryl bromide was partially purified by flashchromatography on silica gel with hexanes:EtOAc (100:0 to 3:1) to give0.381 g of impure4-[(4-bromophenyl)(4,4-dimethylcyclohexylidene)methyl]phenol as an oil.To the impure intermediate aryl bromide (0.37 g) were added tert-butylacrylate (0.60 mL, 0.525 g, 4.1 mmol), Pd(OAc)₂ (0.067 g, 0.30 mmol),Et₃N (0.84 mL, 0.61 g, 6.03 mmol), P(o-tolyl)₃ (0.134 g, 0.44 mmol) andCH₃CN (15 mL). The stirred reaction mixture was heated overnight at 85°C. under a nitrogen atmosphere. The reaction mixture was allowed to coolto room temperature and transferred to a separatory funnel. The reactionmixture was partitioned between EtOAc and H₂O. The layers were separatedand the organic phase was dried (MgSO₄) and filtered. Silica gel wasadded to the filtrate and the solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica gel withhexanes:EtOAc (100:0 to 1:1) as eluant to give 0.24 g (51% from(4-bromophenyl)(4-hydroxyphenyl)methanone) of compound 21 as an oil. ¹HNMR (400 MHz, DMSO-d₆): δ 0.93 (s, 6 H), 1.31 (m, 4 H), 1.45 (s, 9 H),2.16 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.84(d, J=8.4 Hz, 2 H), 7.05 (d, J=8.2 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H),7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1H). LRMS (ESI) m/z 417 (M−H)⁻.

Step 3:(2E)-3-{4-[(4,4-Dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (22)

To a stirred solution of1,1-dimethylethyl(2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(21) (0.24 g, 0.57 mmol) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid(4 mL) at room temperature under a nitrogen atmosphere. The reactionmixture was stirred for 1 h and concentrated in vacuo to give an oil.The oil was dissolved in CH₂Cl₂ and the solvent was removed in vacuo togive a solid which was dried under vacuum at 90° C. to give 0.170 g(82%) of compound 22 as a pale tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ0.93 (s, 6 H), 1.31 (m, 4 H), 2.16 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H),6.65 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.3 Hz, 2 H), 7.05 (d, J=7.9 Hz, 2H), 7.52 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1 H),12.33 (br s, 1 H). The compound was silated prior to EI analysis. HRMS(EI) Calcd for C₃₀H₄₂O₃Si₂: 506.2673 (M⁺). Found: 506.2669.

Example 10 (26)

Step 1: Methyl 4-{[4-(methyloxy)phenyl]carbonyl}benzoate (23)

To a 3-necked round-bottomed flask equipped with a magnetic stir barwere added anisole (31 mL, 30.8 g, 0.285 mol.) and terephthalic acidmonomethyl ester chloride (19.6 g, 0.099 mol.). The flask was equippedwith a powder addition funnel and nitrogen inlet. The powder additionfunnel was charged with AlCl₃ (40.2 g, 0.301 mol.). The reaction mixturewas cooled in an ice-water bath and the AlCl₃ was added slowly,portionwise with stirring, under a nitrogen atmosphere. The ice-waterbath was removed and the stirred reaction mixture was allowed to warm toroom temperature for 3.5 h. The viscous reaction mixture was cooled inan ice-water bath and ice was added very slowly portionwise (Note:significant HCl was released upon addition of ice) followed by the slowaddition of ice-water. The reaction mixture solidified upon quenching.The solid was filtered, washed with water, and allowed to standovernight at RT. The solid washed with water and triturated with hexanes(2×) to give a pink solid. The crude product was recrystallized fromEtOAc to give a white solid. The solid was dried to give 16.0 g (60%) ofcompound 23 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.84 (s, 3H), 3.88 (s, 3 H), 7.08 (d, J=8.8 Hz, 2 H), 7.74 (d, J=8.8 Hz, 2 H),7.77 (d, J=8.3 Hz, 2 H), 8.08 (d, J=8.3 Hz, 2 H).

Step 2: Methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24)

To a 3-necked round-bottomed flask was added AlCl₃ (32 g, 0.24 mol.)followed by anhydrous toluene (250 mL). The flask was equipped with areflux condenser and nitrogen inlet and the suspension was stirred at RTunder a nitrogen atmosphere. To the stirred suspension was added methyl4-{[4-(methyloxy)phenyl]carbonyl}benzoate (23) (16.0 g, 0.059 mol.)portionwise at RT under a nitrogen atmosphere. The reaction mixture washeated at 85° C. with stirring under a nitrogen atmosphere. After 2 h,the oil bath was removed and the reaction mixture was allowed to cool atRT. The reaction mixture was cooled in an ice-water bath and ice wasadded very slowly portionwise (Note: significant HCl evolved uponaddition of ice to the reaction mixture.) followed by the slow additionof ice-water. The reaction mixture was partitioned between EtOAc andwater. The organic phase washed with brine, dried over MgSO₄, filtered,and the filtrate was concentrated to give the crude product as ared-brown solid. The crude product was triturated with hot hexanes andthe brown solid was filtered to give 14.0 g (93%) of compound 24. ¹H NMR(400 MHz, DMSO-d₆): δ 3.88 (s, 3 H), 6.88 (d, J=8.6 Hz, 2 H), 7.65 (d,J=8.7 Hz, 2 H), 7.74 (d, J=8.2 Hz, 2 H), 8.07 (d, J=8.2 Hz, 2 H), 10.51(s, 1 H).

Step 3: Methyl4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoate(25)

To a 1 L 3-necked round-bottomed flask equipped with a reflux condenser,magnetic stir bar, and two nitrogen inlets, was added zinc powder (14.3g, 219 mmoL) followed by anhydrous THF (200 mL). The suspension wasstirred at RT under a nitrogen atmosphere and TiCl₄ (12 mL, 20.8 g, 109mmoL) was added slowly via syringe. (Note: the reaction mixture fumedand warmed during addition of TiCl₄) The stirred reaction mixture washeated at reflux under a nitrogen atmosphere. After 2 h, the oil bathwas removed and the reaction was allowed to stand at RT for 10 min. Theflask was equipped with an addition funnel which was charged with asolution of 3,3,5,5-tetramethylcyclohexanone (15 mL, 13.2 g, 85.7 mmoL)and methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (7.0 g, 27.3 mmoL)in anhydrous THF (150 mL). The flask was placed in the oil bath and thesolution of 3,3,5,5-tetramethylcyclohexanone and methyl4-[(4-hydroxyphenyl)carbonyl]benzoate was added to the reaction mixture.The reaction mixture was heated at reflux for 1.75 h. The oil bath wasremoved and the reaction mixture was allowed to stand at RT for 90 min.The reaction mixture was cooled in an ice-water bath and water (75 mL)was slowly added via an addition funnel followed by 10% aqueous K₂CO₃(75 mL). The quenched reaction mixture was filtered through a pad ofCelite and the pad was washed with EtOAc. The filtrate was partitionedbetween EtOAc and water. The organic phase washed with water followed bybrine, dried over MgSO₄, filtered, and the filtrate was concentrated togive the crude product as an orange liquid. The crude product waspurified by flash chromatography on silica gel with hexanes:EtOAc (100:0to 95:5 to 90:10) to give 8.09 g (78%) of compound 25 as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.85 (s, 6 H), 0.88 (s, 6 H), 1.24(s, 2 H), 1.84 (s, 2 H), 1.92 (s, 2 H), 3.80 (s, 3 H), 6.66 (d, J=8.4Hz, 2 H), 6.93 (d, J=8.5 Hz, 2 H), 7.25 (d, J=8.2 Hz, 2 H), 7.86 (d,J=8.3 Hz, 2 H), 9.31 (s, 1H). LRMS (ESI) m/z 377 (M−H)⁻.

Step 4:4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoicacid (26)

To a round-bottomed flask was added methyl4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoate(25) (8.06 g, 21 mmoL), EtOH (100 mL), and THF (100 mL). To the solutionwas added 1 N aqueous NaOH (200 mL). The reaction mixture was stirred at65° C. under a nitrogen atmosphere for 3 h. The reaction mixture waspartially concentrated in vacuo to remove the EtOH and THF. The aqueousmixture was cooled in an ice-water bath and 1 N aqueous HCl was slowlyadded to pH ˜1. The acidic aqueous suspension was extracted with CH₂Cl₂(1×) followed by EtOAc (3×). Those EtOAc extracts that contained themajority of product, as indicated by TLC, were independently washed withbrine, combined, dried over MgSO₄, filtered, and the filtrate wasconcentrated to give 6.0 g of the crude product as a pale tan solid. TheCH₂Cl₂ extract noted above was concentrated to give 1.9 g of the crudeproduct as an off-white solid. The two crops of crude product werecombined and purified by flash chromatography on silica gel withCH₂Cl₂:MeOH (95:5) to give 6.07 g (79%) of compound 26 as a white solid.A portion of the product was dried under vacuum at 90° C. to give thefollowing ¹H NMR data. ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (s, 6 H), 0.88(s, 6 H), 1.24 (s, 2 H), 1.85 (s, 2 H), 1.92 (s, 2 H), 6.66 (d, J=8.5Hz, 2 H), 6.93 (d, J=8.4 Hz, 2 H), 7.22 (d, J=8.3 Hz, 2 H), 7.84 (d,J=8.3 Hz, 2 H), 9.30 (s, 2 H), 12.78 (br s, 1 H). The compound wassilylated prior to EI analysis. HRMS (EI) Calcd for C₃₀H₄₄O₃Si₂:508.2829 (M⁺). Found: 508.2833.

Example 11 (31)

Step 1: (4-Bromophenyl)[2-methyl-4-(methyloxy)phenyl]methanone (27)

To a mixture of 4-bromobenzoyl chloride (1.12 g, 5.12 mmol) and 3-methylanisole (1.95 mL, 15.47 mmol) at 0° C. was added AlCl₃ (0.83 g, 6.20mmol). The mixture was allowed to warm to RT over 12 h with stirring.Water was added slowly, and the mixture was extracted with CH₂Cl₂. Theorganics were dried with MgSO₄ and concentrated. The crude material waspurified by chromatography on silica gel (EtOAc:hexanes) to yield 1.14 g(73%) of compound 27. ¹H NMR (400 MHz, CDCl₃): δ 2.41 (s, 3H), 3.86 (s,3H), 6.74 (dd, J=2.5 Hz, 8.6 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 7.31 (d,J=8.6 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H).

Step 2: (4-Bromophenyl)(4-hydroxy-2-methylphenyl)methanone (28)

To a solution of (4-bromophenyl)[2-methyl-4-(methyloxy)phenyl]methanone(27) (1.12 g, 3.67 mmoL) in benzene (25 mL) was added AlCl₃ (1.98 g,14.85 mmol). The mixture was heated at 90° C. for 3 h. Upon cooling,water (25 mL) was added, and the mixture was extracted with Et₂O. Theorganics were dried with MgSO₄ and concentrated. The crude material waspurified by chromatography on silica gel (EtOAc:hexanes) to yield 1.32 g(86%) of compound 28. ¹H NMR (400 MHz, DMSO-d₆): δ 2.26 (s, 3H), 6.63(dd, J=2.4 Hz, 8.4 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 7.18 (d, J=8.4 Hz,1H), 7.55 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 10.10 (s, 1H).

Step 3: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-3-methylphenol (29)

To a slurry of zinc powder (1.15 g, 17.59 mmol) in THF (10 mL) was addedTiCl₄ (0.90 mL, 8.21 mmol) dropwise. The mixture was heated at refluxfor 1 h. A mixture of cyclohexanone (0.64 mL, 6.17 mmol) and(4-bromophenyl)(4-hydroxy-2-methylphenyl)methanone (28) (0.60 g, 2.06mmol) in THF (10 mL) was added dropwise and continued to stir at refluxfor 20 min. Upon cooling, the reaction mixture was poured into a 10%aqueous K₂CO₃ solution. The quenched reaction mixture was filteredthrough a pad of Celite and the pad washed with EtOAc. The filtrate wasdried over MgSO₄, filtered, and concentrated to yield 0.60 g (81%) ofthe compound 29. ¹H NMR (400 MHz, CDCl₃): δ 1.50-1.63 (m, 6H), 1.96-2.01(m, 2H), 2.05 (s, 3H), 2.27-2.28 (m, 2H), 4.54 (s, 1H), 6.60-6.62 (m,2H), 6.93-6.95 (m, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H).

Step 4:Ethyl(2E)-3-{4-[cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoate(30)

To a solution of4-[(4-bromophenyl)(cyclohexylidene)methyl]-3-methylphenol (29) (0.60 g,1.68 mmol) in DMF (6 mL) was added ethyl acrylate (0.54 mL, 4.98 mmol),P(o-tolyl)₃ (0.056 g, 0.184 mmol), Et₃N (0.70 mL, 5.02 mmol), andPd(OAc)₂ (0.023 g, 0.10 mmol). The mixture was heated at 140° C. for 30min in a microwave. Upon cooling, water (25 mL) was added, and themixture was extracted with Et₂O (3×20 mL). The organics were combined,dried (MgSO₄), and concentrated. The crude material was purified bychromatography on silica gel (EtOAc:hexanes) to yield 0.13 g, (60%) ofcompound 30. ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.1 Hz, 3H),1.52-1.61 (m, 6H), 1.98-2.01 (m, 2H), 2.06 (s, 3H), 2.32 (m, 2H), 4.24(q, J=7.1 Hz, 2H), 4.78 (s, 1H), 6.36 (d, J=16.1 Hz, 1H), 6.62-6.63 (m,2H), 6.96 (m, 1H), 7.13 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.63(d, J=15.9 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoicacid (31)

To a solution ofethyl(2E)-3-{4-[cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoate(30) (0.42 g, 1.11 mmol) in a mixture of EtOH/THF (1 mL, 4 mL) was addedan aqueous solution of 5M NaOH (1.4 mL, 7.00 mmol). The mixture wasstirred at 85° C. for 4 h. Upon cooling, the mixture was acidified topH=2 with an aqueous solution of 5 M HCl. The mixture was extracted withEtOAc (1×20 mL). The organics were washed with water and brine (1×10 mLeach) and dried with MgSO₄. Concentration yielded 0.39 g (100%) ofcompound 31. ¹H NMR (400 MHz, DMSO-d₆): δ 1.46-1.58 (m, 6H), 1.91-1.96(m, 2H), 1.97 (s, 3H), 2.22-2.26 (m, 2H), 6.43 (d, J=16.1 Hz, 1H), 6.53(m, 2H), 6.83-6.85 (m, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.50 (d, J=16.2 Hz,1H), 7.55 (d, J=8.1 Hz, 2H), 9.16 (s, 1H), 12.32 (s, 1H). LCMS (ESI):m/z 349 (M+H)⁺.

Example 12 (35)

Step 1: (4-Bromophenyl)(4-hydroxy-3-methylphenyl)methanone (32)

To a solution of 4-bromobenzoyl chloride (1.04 g, 4.74 mmol) ando-cresol (0.58 g, 5.33 mmol) in CH₂Cl₂ (20 mL) was added AlCl₃ (0.76 g,5.72 mmol) portion-wise. The mixture was allowed to warm to RT over 12h. Water was added, and the mixture was extracted with CH₂Cl₂. Theorganics were dried with MgSO₄ and concentrated. The crude material waspurified by chromatography on silica gel (EtOAc:hexanes) to yield 0.21 g(15%) of compound 32. ¹H NMR (400 MHz, DMSO-d₆): δ 2.15 (s, 3H), 6.89(d, J=8.3 Hz, 1H), 7.46 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.54 (d, J=1.9 Hz,1H), 7.58 (d, 2H), 7.72 (d, 2H), 10.42 (s, 1H).

Step 2: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-2-methylphenol (33)

The title compound (33) (0.21 g, 82%) was obtained from 32 in a similarmanner previously reported for compound 29. ¹H NMR (400 MHz, CDCl₃): δ1.56-1.62 (m, 6H), 2.18 (s, 3H), 2.21-2.24 (m, 4H), 4.71 (s, 1H), 6.67(d, J=7.7, 1H), 6.80 (d, J=7.9 Hz, 2H), 6.97 (d, J=8.2 Hz, 2H), 7.37 (d,J=8.4 Hz, 2H).

Step 3:Ethyl(2E)-3-{4-[cyclohexylidene(4-hydroxy-3-methylphenyl)methyl]phenyl}-2-propenoate(34)

The title compound (34) (0.13 g, 60%) was obtained from 33 in a similarmanner previously reported for compound 30. ¹H NMR (400 MHz, CDCl₃): δ1.32 (t, J=7.1 Hz, 3H), 1.57 (m, 6H), 2.19 (s, 3H), 2.22-2.25 (m, 4H),4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 1H), 6.38 (d, J=16.1 Hz, 1H), 6.68 (d,J=7.9 Hz, 1H), 6.81 (m, 1H), 6.83 (s, 1H), 7.12 (d, J=8.1 Hz, 2H), 7.42(d, J=8.1 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H).

Step 4:(2E)-3-{4-[cyclohexylidene(4-hydroxy-3-methylphenyl)methyl]phenyl}-2-propenoicacid (35)

The title compound (35) (0.11 g, 96%) was obtained from 34 in a similarmanner previously reported for compound 31. ¹H NMR (400 MHz, DMSO-d₆): δ1.52 (m, 6H), 2.02 (s, 3H), 2.12-2.15 (m, 4H), 6.44 (d, J=16.1 Hz, 1H),6.67-6.71 (m, 3H), 7.05 (d, J=8.2 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.56(d, J=8.2 Hz, 2H), 9.20 (s, 1H), 12.32 (s, 1H). LRMS (APCI): m/z 349(M+H)⁺.

Example 13 (38)

Step 1:4-[(4-Bromophenyl)(tetrahydro-4H-thiopyran-4-ylidene)methyl]phenol (36)

In a 3-neck round-bottomed flask equipped with a condenser and anitrogen inlet, TiCl₄ (0.51 mL, 4.67 mmol) was slowly added to asuspension of zinc powder (0.63 g, 9.60 mmol) in anhydrous THF (13 mL)at room temperature. The reaction was heated at reflux for 2.5 h. Thereaction was taken out of the oil bath then a solution of(4-bromophenyl)(4-hydroxyphenyl)methanone (2)(0.35 g, 1.26 mmol) andtetrahydrothiopyran-4-one (0.44 g, 3.79 mmol) in anhydrous THF (13 mL)was added and the reaction mixture was heated at reflux for 2 h. Thereaction mixture was cooled to room temperature and water (10 mL) added,via syringe, followed by addition of 10% aqueous K₂CO₃ (10 mL). Thereaction mixture was filtered through a pad of Celite and the pad washedwith EtOAc. The filtrate was transferred to a separatory funnel and thelayers were separated. The organic layer washed with brine, dried(MgSO₄), filtered, and the filtrate was concentrated to give an oil. Thecrude product was purified by flash column chromatography on silica gelusing a hexanes:EtOAc gradient (100:0 to 75:25) to give compound 36 as awhite powder (0.323 g, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.38-2.41 (m,2H), 2.45-2.47 (m, 2H), 2.62-2.66 (m, 4H), 6.67 (d, J=8.5 Hz, 2H), 6.86(d, J=8.5 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 9.39(s, 1H).

Step 2:1,1-Dimethylethyl(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-thiopyran-4-ylidene)methyl]phenyl}-2-propenoate(37)

Reagents 36 (0.32 g, 0.886 mmol), t-butyl acrylate (0.78 mL, 5.31 mmol),Pd(OAc)₂ (0.042 g, 0.186 mmol), P(o-tolyl)₃ (0.12 g, 0.381 mmol) andEt₃N (0.74 mL, 5.31 mmol) were added to a flask containing CH₃CN (13 mL)and the reaction mixture was heated at 85° C. for 24 h. The reactionmixture was allowed to cool at RT and partitioned between water andEtOAc. The organic layer was separated, washed with brine, dried(MgSO₄), filtered, and the filtrate was concentrated to give the crudeproduct. The crude product was purified by flash column chromatographyon silica gel using a hexanes:EtOAc gradient (100:0 to 50:50) to givecompound 37 as a yellow foam. ¹H NMR (400 MHz, DMSO-d₆): δ 1.46 (s, 9H),2.65-2.66 (m, 5H), 6.45 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87(d, J=8.5 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.49 (d, J=16.1 Hz, 1H), 7.60(d, J=8.1 Hz, 2H), 9.37 (s, 1H).

Step 3:(2E)-3-{4-[(4-Hydroxyphenyl)(tetrahydro-4H-thiopyran-4-ylidene)methyl]phenyl}-2-propenoicacid (38)

To an ice-cooled solution of 37 (0.16 g, 0.392 mmol) in dry CH₂Cl₂ (2mL) was added TFA (2 mL) slowly. After stirring at 0° C. for 3 h, thereaction mixture was concentrated to give a yellow solid. The crudeproduct was purified by flash column chromatography on silica gel usinga CH₂Cl₂:MeOH gradient (100:0 to 0:100) to give compound 38 a yellowfoam (0.074 g, 54%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.42-2.46 (m, 4H),2.63-2.66 (m, 4H), 6.46 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87(d, J=8.5 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59(d, J=8.2 Hz, 2H), 9.39 (s, 1H), 12.38 (s, 1H). LRMS (ESI) m/z 353(M+H)⁺. HRMS (ESI) Calcd for C₂₁H₂₁O₃S: 353.1211 (M+H)⁺. Found:353.1208.

Example 14 (40)

Step 1:(2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoylchloride (39)

To a mixture of(2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (11) (0.3 g, 0.861 mmol) and dry CH₂Cl₂ (5 mL) was added oxalylchloride (0.15 mL, 1.72 mmol) slowly, followed by DMF (2 drops). Thereaction mixture became a clear solution immediately after the additionof DMF. The reaction mixture was stirred at room temperature for 2 hunder nitrogen. The reaction mixture was concentrated to give 39 as anoily residue that was used without further purification. ¹H NMR (400MHz, DMSO-d₆): δ 1.53 (s, 8H), 2.21-2.25 (m, 4H), 6.48 (d, J=16 Hz, 1H),7.19 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H),7.54 (d, J=16 Hz, 1H), 7.62 (d, J=8.1 Hz, 2H), 9.35 (s, 1H).

Step 2:1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)-3-piperidinecarboxylicacid (40)

To a solution of nipecotic acid (0.058 g, 0.450 mmol) in water (0.5 mL)was added triethylamine (0.125 mL, 0.899 mmol) followed by the slowaddition of a solution of 39 (0.15 g, 0.409 mmol) in THF (3 mL). Thereaction mixture was allowed to stir at RT for 24 h. To the reactionmixture was added 1 N HCl to pH of ˜1. The acidic reaction mixture wasextracted with EtOAc. The organic extract washed with brine, dried(Na₂SO₄), filtered, and the filtrate was concentrated to yield an oilyresidue. The crude material was purified by reverse phase preparativeHPLC using a C18 column and a CH₃CN:H₂O gradient (10:90 to 100:0) with0.05% TFA as a modifier to give compound 40 as a white powder (87 mg,47%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.40-1.47 (m, 1H), 1.57 (s, 8H),1.66-1.73 (m, 2H), 1.96-1.98 (m, 1H), 2.24-2.30 (m, 4H), 2.39-2.44 (m,1H), 3.14-3.21 (m, 2H), 3.92-3.95 (m, 1H), 4.18-4.22 (m, 1H), 6.69 (d,J=8.3 Hz, 2H), 6.93 (d, J=8.3 Hz, 2H), 7.04 (d, J=15.3 Hz, 1H), 7.13 (d,J=8 Hz, 2H), 7.39 (d, J=15.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 8.79 (s,1H). HRMS (ESI) Calcd for C₂₉H₃₄NO₄: 460.2488 (M+H)⁺. Found: 460.2490.

Example 15 (41)

Step 1:1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)-4-piperidinecarboxylicacid (41)

To a solution of isonipecotic acid (0.057 g, 0.44 mmol) in water (0.5mL) was added Et₃N (0.12 mL, 2.2 eq) followed by a solution of 39 (0.147g, 0.399 mmol) in dry THF (3 mL). The reaction mixture was stirred at RTunder nitrogen for 24 h. Isonipecotic acid (1.1 eq, 0.44 mmol) was addedand the reaction mixture was stirred at RT for 24 h. The reactionmixture was heated at 45° C. for 1.3 h and then heated at 55° C. for 24h. The reaction mixture was allowed to cool at RT. To the reactionmixture was added 1 N HCl to pH of ˜1. The acidic reaction mixture wasextracted with EtOAc. The organic layer washed with brine, dried(Na₂SO₄), filtered, and the filtrate was concentrated. The crude productwas purified by preparative reverse phase HPLC using a C18 column and aCH₃CN:H₂O gradient (10:90 to 100:0) with 0.05% TFA as a modifier to givecompound 41 as a powder (0.018 g, 10%). ¹H NMR (400 MHz, DMSO-d₆): δ1.51 (s, 9H), 1.82-1.85 (m, 2H), 2.19-2.23 (m, 4H), 2.78-2.81 (m, 1H),3.13-3.16 (m, 1H), 4.12-4.15 (m, 1H), 4.25-4.28 (m, 1H), 6.65 (d, J=8.4Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.17 (d, J=15.4Hz, 1H), 7.40 (d, J=15.4 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.28 (s, 1H),12.24 (d, 1H). HRMS (ESI) Calcd for C₂₉H₃₄NO₄: 460.2488 (M+H)⁺. Found:460.2497.

Example 16 (42)

Step 1:1-((2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoyl)proline(42)

To a solution of L-proline (0.051 g, 0.44 mmol) in water (0.5 mL) wasadded Et₃N (0.12 mL, 2.2 eq) followed by a solution of 39 (0.147 g,0.399 mmol) in dry THF (3 mL). The reaction mixture was stirred at RTunder nitrogen for 24 h. L-proline (0.44 mmol, 1.1 eq,) was added andthe reaction mixture was allowed to stir for another 24 h. The reactionmixture was heated at 45° C. for 1.3 h and then heated at 55° C. for 24h. The reaction mixture was allowed to cool to room temperature. To thereaction mixture was added 1 N HCl to a pH of ˜1. The acidic reactionmixture was extracted with EtOAc. The organic layer was separated,washed with brine, dried (Na₂SO₄), filtered, and the filtrate wasconcentrated. The crude product was purified preparative reverse phaseHPLC using a C18 column and a CH₃CN:H₂O gradient (10:90 to 100:0) and0.05% TFA as a modifier to give a powder (0.052 g, 30%). ¹H NMR (400MHz, DMSO-d₆): δ 1.56 (s, 8H), 1.92 (s, 3H), 2.21-2.29 (m, 5H), 3.64 (s,3H), 4.48 (s, 1H), 6.69 (d, J=8.6 Hz, 2H), 6.81 (br, 1H), 6.93 (d, J=8.5Hz, 2H), 7.14 (d, J=8.2 Hz, 2H), 7.42 (d, J=15.4 Hz, 1H), 7.50 (d, J=7.9Hz, 2H). HRMS (ESI) Calcd for C₂₈H_(32 N)O₄: 446.2331 (M+H)⁺. Found:446.2321

Example 17 (45)

Step 1: 4-[Bicyclo[3.3.1]non-9-ylidene(4-bromophenyl)methyl]phenol (43)

In a 3-neck round-bottomed flask equipped with a reflux condenser and anitrogen inlet, TiCl₄ (0.51 mL, 4.67 mmol) was slowly added to asuspension of zinc powder (0.63 g, 9.60 mmol) in dry THF (13 mL) at roomtemperature. The reaction mixture was heated at reflux for 2.5 h. Thereaction mixture was taken out of the oil bath and a solution of(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.35 g, 1.26 mmol) andbicyclo[3.3.1]nonan-9-one (0.52 g, 3.79 mmol) in dry THF (13 mL) wasadded. The reaction mixture was heated at reflux for 2 h. The reactionmixture was allowed to cool at RT. Water (10 mL) was added to thereaction mixture via a syringe followed by 10% K₂CO₃ (10 mL). Thereaction mixture was filtered through a pad of Celite. The pad of Celitewashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic layer washed with brine,dried (MgSO₄), filtered, and the filtrate was concentrated to give anoily residue. The crude product was adsorbed onto silica and purified byflash column chromatography using SiO₂ and a hexanes:EtOAc gradient(100:0 to 75:25) to afford compound 43 as a white powder (0.32 g, 67%).¹H NMR (400 MHz, DMSO-d₆): δ 1.50-1.54 (m, 2H), 1.71-1.73 (m, 8H),1.93-1.99 (m, 2H), 2.60 (s, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 9.32 (s, 1H).

Step 2:1,1-Dimethylethyl(2E)-3-{4-[bicyclo[3.3.1]non-9-ylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate(44)

Compound 43 (0.32 g, 0.834 mmol), t-butyl acrylate (0.734 mL, 5.01mmol), P(o-tolyl)₃ (0.11 g, 0.359 mmol), Pd(OAc)₂ (0.0394 g, 0.175 mmol)and Et₃N (0.7 mL, 5.01 mmol) were added to a flask containing CH₃CN (13mL) and the stirred reaction mixture was heated at 85° C. for 24 h undera nitrogen atmosphere. The reaction mixture was allowed to cool at RTand then partitioned between water and EtOAc. The layers were separated,and the organic phase washed with brine, dried (MgSO₄), filtered, andthe filtrate was concentrated to give an oily residue. The crude oil wasadsorbed onto silica and purified by flash column chromatography onsilica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to givecompound 44 as a yellow foam (0.33 g, 92%). ¹H NMR (400 MHz, DMSO-d₆): δ1.45-1.53 (m, 10H), 1.72-1.73(m, 7H), 1.96-2.01(m, 2H), 2.53-2.64 (m,4H), 6.42 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.3 Hz,2H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz,2H), 9.30 (s, 1H).

Step 3:(2E)-3-{4-[bicyclo[3.3.1]non-9-ylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (45)

To an ice-cooled solution of 44 (0.32 g, 0.755 mmol) in CH₂Cl₂ (4 mL)was added TFA (4 mL) slowly. The stirred reaction mixture was allowed towarm to RT over a period of 3 h. The reaction mixture was concentratedto give a yellow solid. The solid was dissolved in toluene, and thesolution was concentrated to give a powder. The powder was trituratedwith CH₂Cl₂ and dried to give compound 45 as a tan powder (0.21 g, 74%).¹H NMR (400 MHz, DMSO-d₆): δ 1.50-1.53 (m, 2H), 1.72 (s, 8H), 1.93-2.01(m, 2H), 2.53-2.60 (m, 2), 6.43 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.4 Hz,2H), 6.88 (d, J=8.3 Hz, 2H), 7.09 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.0 Hz,1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H), 12.33 (s, 1H). The compoundwas silated prior to EI analysis. HRMS (EI) Calcd for C₃₁H₄₂O₃Si₂:518.2673 (M⁺). Found: 518.2685.

Example 18 (48)

Step 1: 4-[(4-Bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol(46)

Zinc powder (0.759 g, 11.6 mmole) was suspended in THF (13 mL). TiCl₄(0.640 mL, 5.84 mmole) was added dropwise and the resulting mixture washeated to reflux for 60 min. A solution of(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.404 g, 1.46 mmole) andtetrahydropyran-4-one (0.405 mL, 4.38 mmole) in THF (2 mL) was added.The resulting mixture was heated to reflux for 2 h, then was allowed tocool to RT. A 10% aqueous solution of K₂CO₃ (25 mL) was added and themixture was filtered through a pad of Celite. The filtrate was separatedand the aqueous layer was extracted with EtOAc (2×20 mL). The organicswere washed with water (25 mL) and brine (25 mL), then dried (MgSO₄) andconcentrated. The residue was purified by silica gel chromatography(Isco Sg100c, RediSep 12 g cartridge and a gradient consisting of 10%EtOAc:hexanes for 5 min, 10% to 30% EtOAc:hexanes over 15 min, then 30%EtOAc:hexanes for 5 min) to provide 0.31 g (62%) of compound 46 as awhite solid. ¹H NMR (CDCl₃): δ 7.41 (d, J=8.3 Hz, 2H), 6.97 (d, J=8.6Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 6.75 (d, J=8.3 Hz, 2H), 4.97 (s, 1H),3.72 (dd, J=10.0, 5.0 Hz, 4H), 2.40 (t, J=5.0 Hz, 2H), 2.36 (t, J=5.0Hz, 2H).

Step 2: tert-Butyl(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate(47)

4-[(4-Bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol (L)(0.106 g, 0.307 mmole) was dissolved in DMF (1 mL). tert-Butyl acrylate(0.090 mL, 0.614 mmole), P(o-tolyl)₃ (0.0099 g, 0.0325 mmole) and Et₃N(0.130 mL, 0.933 mmole) were added followed by Pd(OAc)₂ (0.0037 g,0.0165-mmole). The mixture was heated to 160° C. in a microwavesynthesizer for 30 min then was cooled to RT. Water (20 mL) was addedand the mixture was extracted with Et₂O (3×10 mL). The organics weredried (MgSO₄) and concentrated. The residue was purified by silica gelchromatography (Isco Sg100c, RediSep 12 g cartridge, 15% EtOAc:hexanesfor 5 min, 15% to 40% EtOAc:hexanes over 15 min, 40% EtOAc:hexanes for 5min to yield 0.071 g (59%) of 47 as a white solid. ¹H NMR (CDCl₃): δ7.55 (d, J=16.0 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H),6.97 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.32 (d, J=16.0 Hz, 1H),5.01 (s, 1H), 3.74 (m, 4H), 2.40 (dd, J=11.1, 5.6 Hz, 4H), 1.53 (s, 9H).

Step 3:(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoicacid (48)

tert-Butyl(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate(47) (0.071 g, 0.182 mmol) was dissolved in CH₂Cl₂ (1 mL) and TFA (1mL). The solution was stirred at RT for 4 h, then was concentrated. Theresidue was recrystallized from EtOAc to provide 0.020 g (33%) ofcompound 48 as a tan solid. ¹H NMR (DMSO-d₆): δ 12.34 (s, 1H), 9.37 (s,1H), 7.58 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.07 (d, J=8.2 Hz,2H), 6.85 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.45 (d, J=16.0 Hz,1H), 3.59 (m, 4H), 2.25 (m, 4H). LRMS (ESI): m/z 335 (M−H)⁻.

Example 19 (51)

Step 1: 4-[(4-Bromophenyl)cyclooctylidene)methyl]phenol (49)

Following the procedure described for compound 46, zinc powder (0.764 g,11.7 mmole), TiCl₄ (0.640 mL, 5.84 mmole),(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.404 g, 1.46 mmole) andcyclooctanone (0.580 mL, 4.40 mmole), yielded 332 mg (61%) of compound49 as a white solid. ¹H NMR (CDCl₃): δ 7.39 (d, J=8.3 Hz, 2H), 7.04 (d,J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 4.61 (s,1H), 2.25 (m, 4H), 1.63 (m, 2H), 1.52 (m, 8).

Step 2: tert-Butyl(2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoate(50)

Following the procedure described for compound 47,4-[(4-bromophenyl)cyclooctylidene)methyl]phenol (49) (0.105 g, 0.283mmole), tert-butyl acrylate (0.084 mL, 0.573 mmole), P(o-tolyl)₃ (0.0097g, 0.0319 mmole), Et₃N (0.125 mL, 0.897 mmole), Pd(OAc)₂ (0.0042 g,0.0187 mmole) and DMF (1.5 mL) yielded 0.059 g (49%) of compound 50 as awhite solid. ¹H NMR (CDCl₃): δ 7.54 (d, J=15.9 Hz, 1H), 7.41 (d, J=8.2Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4Hz, 2H), 6.30 (d, J=15.9 Hz, 1H), 4.73 (s, 1H), 2.27 (m, 4H), 1.64 (m,2H), 1.57 (m, 8H), 1.52 (s, 9H).

Step 3:(2E)-3-{4-[Cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoicacid (51)

tert-Butyl(2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoate(50) (0.0586 g, 0.140 mmole) was dissolved in methylene chloride (1 mL)and trifluoroacetic acid (1 mL). The solution was stirred at RT for 4 h,then was concentrated. The residue was recrystallized from EtOAc toprovide compound 51 (0.013 g, 25%) as a white solid. ¹H NMR (DMSO-d₆): δ12.32 (s, 1H), 9.27 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.51 (d, J=16.1 Hz,1H), 7.14 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz,2H), 6.43 (d, J=16.1 Hz, 1H), 2.18 (m, 4H), 1.59 (m, 2H), 1.45 (m, 8H).LRMS (ESI): m/z 361 (M−H)⁻.

Example 20 (55)

Step 1: 2,2,6,6-Tetramethyltetrahydro-4H-pyran-4-one (52)

Phorone (9.967 g, 72.1 mmole) was suspended in 1 N aqueous hydrochloricacid (100 mL). The mixture was heated to 40° C. for 7 days, then wascooled to RT. The mixture was extracted with ether (3×25 mL). Theorganics were dried (MgSO₄) and concentrated. The residue was purifiedby silica gel chromatography (Isco Sg100c, RediSep 120 g cartridge, 5%EtOAc:hexanes for 5 min, 5% to 15% EtOAc:hexanes over 10 min, 15% EtOAcfor 5 min, 15% to 25% EtOAc:hexanes over 10 min, 25% EtOAc:hexanes for 5min) to provide 52 (2.80 g, 25%) as a pale yellow liquid. ¹H NMR(CDCl₃): δ 2.43 (s, 4H), 1.32 (s, 12H).

Step 2:4-[(4-Bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol(53)

Following the procedure described for compound 46, zinc powder (0.957 g,14.6 mmole), TiCl₄ (0.800 mL, 7.30 mmole),(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.512 g, 1.85 mmole) and2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.851 mL, 5.45mmole), afforded 0.564 g (76%) of 53 as a white foamy solid. ¹H NMR(CDCl₃): δ 7.41 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.01 (d,J=8.4 Hz, 2H), 6.76 (d, J=8.3 Hz, 2H), 4.99 (s, 1H), 2.24 (s, 2H), 2.20(s, 2H), 1.22 (s, 6H), 1.21 (s, 6H).

Step 3:Ethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate(54)

Following the procedure described for compound 47,4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol(53) (0.152 g, 0.379 mmole), ethyl acrylate (0.125 mL, 1.15 mmole),P(o-tolyl)₃ (0.0126 g, 0.041 mmole), Et₃N (0.160 mL, 1.15 mmole),Pd(OAc)₂ (0.0044 g, 0.020 mmole) and DMF (1.5 mL) afforded 0.110 g (69%)of compound 54 as a white solid. ¹H NMR (CDCl₃): δ 7.65 (d, J=16.0 Hz,1H), 7.45 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.03 (d, J=8.4 Hz,2H), 6.77 (d, J=8.4 Hz, 2H), 6.40 (d, J=16.0 Hz, 1H), 4.84 (s, 1H), 4.25(q, J=7.1 Hz, 2H), 2.25 (s, 2H), 2.24 (s, 2H), 1.34 (t, J=7.1 Hz, 3H),1.23 (s, 6H), 1.22 (s, 6H).

Step 4:(2E)-3-{4-[(4-Hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoicacid (55)

Ethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate(54) (0.1095 g, 0.260 mmole) was dissolved in ethanol (5 mL). Potassiumhydroxide (0.260 mL of a 3 M aqueous solution, 0.780 mmole) was addedand the mixture was heated to 75° C. for 2.5 h. The solution was cooledto RT and concentrated. Water (25 mL) was added and the mixture wasextracted with ether (10 mL). The organics were thrown out and theaqueous layer was treated with 1 N aqueous HCl to pH=3. The resultingmixture was extracted with methylene chloride (3×10 mL). The organicswere dried (Na₂SO₄) and concentrated to provide 0.097 g (95%) ofcompound 55 as a pale yellow solid. ¹H NMR (DMSO-d₆): δ 12.33 (s, 1H),9.34 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.15 (d,J=8.2 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.44 (d,J=15.9 Hz, 1H), 2.14 (s, 2H), 2.11 (s, 2H), 1.11 (s, 6H), 1.10 (s, 6H).LRMS (ESI): m/z 391 (M−H)⁻.

Example 21 (58)

Step 1: N-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetamide (56)

A round-bottomed flask was charged with 4-acetamidobenzoyl chloride(0.95 g, 4.57 mmol), anisole (0.60 mL, 5.48 mmoL) and CH₂Cl₂ (15 mL).Cooled in an ice bath, AlCl₃ (0.93 g, 6.85 mmol) was added in portions.The mixture was stirred at 0° C. for 4 h. The resulting dark brownsolution was poured into 1 N HCl (25 mL) with ice and the mixture wasextracted with EtOAc (2×60 mL). The combined EtOAc extract was washedwith water, brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated to give brown solid. The crude product was purified bychromatography on a silica gel column eluted with hexanes:EtOAc (1:1) togive 0.55 g (45%) of compound 56 as light brown solid. mp 160-162° C. ¹HNMR (400 MHz, CDCl₃): δ 2.22 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz,2H), 7.34 (br s, 1H), 7.55-7.65 (m, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.79(d, J=8.8 Hz, 2H). LCMS (ESI): m/z 270 (M+H)⁺, 268 (M−H)⁻.

Step 2:N-{4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide(57)

To a stirred suspension of zinc powder (0.39 g, 5.94 mmol) in THF (15mL) was slowly added TiCl₄ (0.33 mL, 2.97 mmol) via syringe at RT undera nitrogen atmosphere. The mixture was heated at reflux for 2 h. Asolution of N-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetamide (56)(0.20 g, 0.74 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.35 g, 2.23mmol) in THF (4 mL) was added to the mixture. The reaction mixture washeated at reflux with stirring under a nitrogen atmosphere for 1 h. Thereaction mixture was allowed to cool to room temperature. To thereaction mixture was slowly added 10% aqueous K₂CO₃ (15 mL). Thereaction mixture was filtered through a pad of Celite and the pad washedwith EtOAc (100 mL). The filtrate was transferred to a separatory funneland the layers were separated. The aqueous layer was further extractedwith EtOAc (25 mL). The combined organic phase washed with water, brine,dried (Na₂SO₄) filtered, and the filtrate was concentrated to give thecrude product as yellow oil. The crude product was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 40% EtOAc:hexanes to give 0.27 g (93%) of compound 57 ascolorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ 0.91 (s, 6H), 0.92 (s,6H), 1.27 (s, 2H), 1.96 (s, 2H), 1.97 (s, 2H), 2.16 (s, 3H), 3.78 (s,3H), 6.80 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.5 Hz,2H), 7.39 (d, J=8.5 Hz, 2H). LCMS (ESI): m/z 392 (M+H)⁺, 390 (M−H)⁻.

Step 3:N-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide(58)

N-{4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide(57) (0.27 g, 0.69 mmol) was dissolved in CH₂Cl₂ (25 mL). The mixturewas cooled to −10° C. in an ice-acetone bath. To this solution was added1 M BBr₃ in CH₂Cl₂ (2.1 mL, 2.07 mmol). The reaction mixture was stirredat −10° C. to 0° C. for 3 h, then poured onto ice, extracted with EtOAc(2×60 mL). The combined organic extract washed with water, brine anddried over Na₂SO₄. Upon concentration and trituration with 1:1hexanes:CH₂Cl₂, compound 58 was obtained as a light brown solid (0.10 g,39%). mp 118-121° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.85 (s, 6H), 0.86 (s,6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 1.98 (s, 3H), 6.64 (d,J=8.3 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 9.24 (s, 1H), 9.84 (s, 1H); LCMS (ES): m/z 378 (M+H)⁺,376 (M−H)⁻. Anal. Calcd for C₂₅H_(31 N)O₂.⅓H₂O: C, 78.29; H, 8.32; N,3.65; Found: C, 78.33; H, 8.26; N, 3.62.

Example 22 (60)

Step 1: tert-Butyl(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoate(59)

Following the procedure described for compound 47, from4-[(4-bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol (46)(0.101 g, 0.293 mmole), tert-butyl methacrylate (0.095 mL, 0.585 mmole),P(o-tolyl)₃ (0.0092 g, 0.0302 mmole), Et₃N (0.125 mL, 0.897 mmole),Pd(OAc)₂ (0.0038 g, 0.0169 mmole) and DMF (1.5 mL) yielded compound 59(0.070 g, 59%) as a white solid. ¹H NMR (CDCl₃): δ 7.55 (s, 1H), 7.31(d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.76(d, J=8.5 Hz, 2H), 4.91 (s, 1H), 3.73 (m, 4H), 2.41 (m, 4H), 1.58 (s,3H), 1.54 (s, 9H).

Step 2:(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoicacid (60)

tert-Butyl(2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoate(59) (0.0702 g, 0.173 mmole) was dissolved in CH₂Cl₂ (1 mL) and TFA (1mL). The solution was stirred at RT for 4 h, then was concentrated. Theresidue was triturated with CH₂Cl₂ to provide compound 60 (0.029 g, 47%)as a tan solid. ¹H NMR (DMSO-d₆): δ 12.49 (br s, 1H), 9.38 (s, 1H), 7.54(s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 3.60 (m, 4H), 2.25 (m, 4H), 2.01 (s,3H). LRMS (ESI): m/z 349 (M−H)⁻.

Example 23 (62)

Step 1:[4-({2-[(2-Hydroxyethyl)oxy]ethyl}oxy)phenyl](4-hydroxyphenyl)methanone(61)

To a solution of 4,4′-dihydroxybenzophenone (3.0 g, 13.9 mmol) in DMF(30 mL) was added Cs₂CO₃ (13.55 g, 41.6 mmol). The mixture was heated at80° C. under nitrogen for 1 h. The stirred reaction was cooled to roomtemperature and NaI (2.08 g, 13.9 mmol) was added, followed by dropwiseaddition of a solution of 2-(2-chloroethoxy)ethanol (1.63 mL, 15.3 mmol)in DMF (7 mL). The reaction mixture was heated at 80° C. under nitrogenovernight. The mixture was cooled to room temperature and quenched withsaturated aqueous NH₄Cl (100 mL), then extracted with EtOAc (3×60 mL).The organic layers were combined and washed with water, brine, and driedover Na₂SO₄, then concentrated to a light brown oil which was furtherpurified by chromatography on a silica gel column eluted with a gradientfrom hexanes to 95% EtOAc:hexanes to give a light brown oil whichcontained some DMF. The residue was dissolved in EtOAc (100 mL) andfurther washed with water (2×50 mL), saturated aqueous CuSO₄ (50 mL),water (50 mL) and brine (50 mL). The EtOAc solution was dried (Na₂SO₄)and concentrated to 15 mL and 30 mL of hexanes added. A white solidprecipitated and washed with 1:1 hexanes:EtOAc to afford compound 61(1.90 g, 45%). mp 126-127° C. ¹H NMR (400 MHz, CD₃OD): δ 3.60-3.65 (m,2H), 3.65-3.70 (m, 2H), 3.85-3.90 (m, 2H), 4.20-4.25 (m, 2H), 6.87 (d,J=8.6 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.73 (d,J=8.8 Hz, 2H). LRMS (APCI): m/z, 303 (M+H)⁺, 301 (M−H)⁻.

Step 2:4-[[4-({2-[(2-Hydroxyethyl)oxy]ethyl}oxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(62)

To a stirred suspension of Zn (0.59 g, 9.00 mmol) in THF (10 mL) wasadded TiCl₄ (0.50 mL, 4.50 mmol) dropwise. The mixture was refluxedunder nitrogen for 2.5 h. After cooling to room temperature, a solutionof 61 (0.34 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g,3.37 mmol) in THF (15 mL) was added and the reaction mixture refluxedfor an additional 2.5 h. Cooled to room temperature, the reaction wasquenched with 10% K₂CO₃ (20 mL). The quenched reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc (100 mL).The filtrate was transferred to a separatory funnel, the layers wereseparated, and the aqueous phase was extracted with EtOAc (50 mL). Thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated to give a pale yellow oil. The residue was further purifiedby chromatography on a silica gel column eluted with a gradient fromhexanes to 55% EtOAc:hexanes to give 62 as a white solid (0.36 g, 75%).mp 122-124° C. ¹H NMR (400 MHz, CD₃OD): δ 0.91 (s, 6H), 0.92 (s, 6H),1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70(m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.67 (d, J=8.4 Hz, 2H),6.83 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H).LRMS (APCI): m/z 425 (M+H)⁺, 423 (M−H)⁻. Anal. Calcd for C₂₇H₃₆O₄: C,76.38; H, 8.55; Found: C, 76.17; H, 8.65.

Example 24 (64)

Step 1:Diethyl(E)-2-{-4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}ethenylphosphonate(63)

Following the procedure described for compound 47, from4-[(4-bromophenyl)cycloheptylidene)methyl]phenol (9)(0.146 g, 0.409mmole), diethyl vinylphosphonate (0.190 mL, 1.24 mmole), P(o-tolyl)₃(0.0123 g, 0.0404 mmole), Et₃N (0.170 mL, 1.22 mmole), Pd(OAc)₂ (0.0046g, 0.0205 mmole) and DMF (1.5 mL) yielded 63 (0.0502 g, 28%) as a whitesolid. ¹H NMR (DMSO-d₆): δ 9.28 (s, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.30(dd, J=22.7, 17.6 Hz, 1H), 7.11 (d, J=8.3 Hz, 2H), 6.89 (d, J=8.4 Hz,2H), 6.65 (d, J=8.4 Hz, 2H), 6.48 (dd, J=22.7, 17.6 Hz, 1H), 4.01-3.91(m, 4H), 2.20 (m, 4H), 1.50 (m, 8H), 1.21 (m, 6H).

Step 2: Ethyl hydrogen(E)-2-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}ethenylphosphonate(64)

To a solution ofdiethyl(E)-2-{-4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}ethenylphosphonate(63) (0.051 g, 0.115 mmol) in EtOH (4 mL) was added aqueous NaOH (1 mLof a 5M solution, 5 mmol). The solution was heated to reflux for 4 h,then cooled to RT and concentrated. The residue was dissolved in water(1 mL) and the pH adjusted to ˜2 with 1 N aqueous HCl. The mixture wasextracted with EtOAc (2×10 mL). The organics were dried (Na₂SO₄) andconcentrated to provide compound 64 (0.041 g, 86%) as a waxy yellowsolid. ¹H NMR (DMSO-d₆): δ 9.28 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.20(dd, J=22.0 Hz, 17.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.4 Hz,2H), 6.65 (d, J=8.4 Hz, 2H), 6.41 (t, J=17.6 Hz, 1H), 3.90-3.84 (m, 2H),2.20 (m, 4H), 1.50 (m, 8H), 1.18 (t, J=6.9 Hz, 3H). LRMS (ESI): m/z 411(M−H)⁻.

Example 25 (69)

Step 1: (4-Bromo-3-methylphenyl)(4-methoxyphenyl)methanone (65)

AlCl₃ (3.63 g, 27.2 mmol) was added portionwise to4-bromo-3-methylbenzoyl chloride (5.30 g, 22.7 mmol) dissolved inanisole (7 mL) at 0° C. The reaction mixture was warmed to RT, stirredfor 1 h, and then cooled to 0° C. Water (200 mL) was cautiously addeddropwise, and the mixture was extracted with ether (3×100 mL). Thecombined ethereal extracts were washed with water (250 mL), brine (250mL), and dried over MgSO₄. Concentration followed by flashchromatography (20:1 to 5:1 hexanes:EtOAc) afforded 6.42 g (93%) of 65as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.45 (s, 3H), 3.88 (s, 3H),6.96 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 1H), 7.62 (m, 2H), 7.79 (d,J=8.8 Hz, 2H).

Step 2: (4-Bromo-3-methylphenyl)(4-hydroxyphenyl)methanone (66)

A mixture of 65 (2.00 g, 6.55 mmol) and AlCl₃ (3.50 g, 26.2 mmol) wererefluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100mL) was cautiously added dropwise, and the mixture was extracted withEt₂O (3×100 mL). The combined ethereal extracts were washed with water(200 mL), brine (200 mL), and dried over MgSO₄. Concentration afforded1.78 g (93%) of 66 that was used without further purification. ¹H NMR(400 MHz, CDCl₃): δ 2.45 (s, 3H), 5.68 (br s, 1H), 6.90 (d, J=8.6 Hz,2H), 7.40 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.63 (m, 2H), 7.75 (d, J=8.6 Hz,2H).

Step 3: 4-[(4-Bromo-3-methylphenyl)(cyclohexylidene)methyl]phenol (67)

Titanium tetrachloride (2.70 mL, 24.5 mmol) was added dropwise to asuspension of zinc powder (3.24 g, 49.5 mmol) in anhydrous THF (60 mL)at RT. After refluxing for 1 h, a mixture of 66 (1.78 g, 6.11 mmol) andcyclohexanone (1.80 g, 18.3 mmol) dissolved in THF (20 mL) was addeddropwise. Refluxing was continued for 30 min. The reaction mixture wascooled to RT and filtered through Celite. Water (250 mL) was added andthe mixture was extracted with Et₂O (3×100 mL). The combined etherealextracts were washed with water (200 mL), brine (200 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 1.85 g (85%) of 67 as an orange solid. ¹H NMR(400 MHz, CDCl₃): δ 1.58 (m, 6H), 2.20 (m, 4H), 2.32 (s, 3H), 5.95 (brs, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.1 Hz, 2.0 Hz, 1H), 6.95(m, 3H), 7.40 (d, J=8.1 Hz, 1H).

Step 4:1,1-Dimethylethyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]-2-methylphenyl}-2-propenoate(68)

A mixture of 67 (380 mg, 1.06 mmol), tert-butyl acrylate (0.369 mL, 2.55mmol), Pd(OAc)₂ (15.0 mg, 0.067 mmol), P(o-tolyl)₃ (40.0 mg, 0.131mmol), and Et₃N (0.520 mL, 3.73 mmol) were heated under microwaveirradiation at 140° C. for 30 min. Water (30 mL) was added and themixture was extracted with Et₂O (3×20 mL). The combined etherealextracts were washed with water (30 mL), brine (30 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 220 mg (51%) of 68. ¹H NMR (400 MHz, CDCl₃): δ1.52 (s, 9H), 1.58 (m, 6H), 2.22 (m, 4H), 2.34 (s, 3H), 4.85 (s, 1H),6.25 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.90-6.97 (m, 4H), 7.44(d, J=8.1 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-2-methylphenyl}-2-propenoicacid (69)

Trifluoroacetic acid (2.0 mL) was added dropwise to 68 (210 mg, 0.519mmol) dissolved in CH₂Cl₂ (2 mL) at 0° C. The reaction mixture wasstirred at RT for 3 h and the volatiles were removed under reducedpressure. The residue was chromatographed on silica gel (20:1CH₂Cl₂:MeOH) and recrystallized (EtOAc:hexanes) to afford 138 mg (76%)of 69 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.51 (br s,6H), 2.13 (m, 4H), 2.30 (s, 3H), 6.35 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.2Hz, 2H), 6.82-6.91 (m, 4H), 7.59 (d, J=7.9 Hz, 1H), 7.75 (d, J=16.0 Hz,1H), 9.31 (s, 1H), 12.36 (br s, 1H). LRMS (ESI): m/z 349 (M+H)⁺.

Example 26 (74)

Step 1: (4-Bromo-2-chlorophenyl)(4-methoxyphenyl)methanone (70)

Oxalyl chloride (4.10 mL, 47.3 mmol) was added dropwise to4-bromo-2-chlorobenzoic acid (5.57 g, 23.7 mmol) dissolved in CH₂Cl₂(100 mL). After stirring overnight at RT, additional oxalyl chloride(2.05 mL, 23.7 mmol) was added and the reaction mixture was refluxed for26 h. The volatiles were removed and the residue was dissolved inanisole (10 mL) and cooled to 0° C. AlCl₃ (4.50 g, 33.7 mmol) was addedportionwise and the reaction mixture was stirred for 2 h. Water (200 mL)was cautiously added dropwise, and the mixture was extracted with Et₂O(3×100 mL). The combined ethereal extracts were washed with water (250mL), brine (250 mL), and dried over MgSO₄. Concentration followed byflash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 6.60 g (90%)of 70 as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 3.87 (s, 3H),6.93 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.1 Hz, 1.8Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H).

Step 2: (4-Bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone (71)

A mixture of 70 (2.00 g, 6.14 mmol) and AlCl₃ (3.50 g, 26.2 mmol) wererefluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100mL) was cautiously added dropwise, and the mixture was extracted withEt₂O (3×100 mL). The combined ethereal extracts were washed with water(200 mL), brine (200 mL), and dried over MgSO₄. Concentration followedby flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.42 g(74%) of 71. ¹H NMR (400 MHz, CDCl₃): δ 5.97 (br s, 1H), 6.89 (d, J=8.8Hz, 2H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.1 Hz, 1.7 Hz, 1H), 7.64(d, J=1.7 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H).

Step 3: 4-[(4-Bromo-2-chlorophenyl)(cyclohexylidene)methyl]phenol (72)

TiCl₄ (2.01 mL, 18.2 mmol) was added dropwise to a suspension of zincpowder (2.41 g, 36.9 mmol) in anhydrous THF (60 mL) at RT. Afterrefluxing for 1 h, a mixture of 71 (1.42 g, 4.56 mmol) and cyclohexanone(1.34 g, 13.7 mmol) dissolved in THF (20 mL) was added dropwise.Refluxing was continued for 30 min. The reaction mixture was cooled toRT and filtered through Celite. Water (250 mL) was added and the mixturewas extracted with Et₂O (3×100 mL). The combined ethereal extracts werewashed with water (200 mL), brine (200 mL), and dried over MgSO₄.Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 1.61 g (93%) of compound 72 as a light greenoil. ¹H NMR (400 MHz, CDCl₃): δ 1.59 (m, 6H), 1.97 (m, 2H), 2.28 (m,2H), 4.93 (br s, 1H), 6.72 (d, J=8.6 Hz, 2H), 7.04 (m, 3H), 7.32 (dd,J=8.2 Hz, 2.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H).

Step 4:1,1-Dimethylethyl(2E)-3-{3-chloro-4-[cyclohexylidene(4-hydroxyphenyl)-methyl]phenyl}-2-propenoate(73)

A mixture of 72 (459 mg, 1.22 mmol), tert-butyl acrylate (0.369 mL, 2.55mmol), Pd(OAc)₂ (15.0 mg, 0.067 mmol), P(o-tolyl)₃ (40.0 mg, 0.131mmol), and Et₃N (0.520 mL, 3.73 mmol) were heated under microwaveirradiation at 140° C. for 30 min. Water (30 mL) was added and themixture was extracted with Et₂O (3×20 mL). The combined etherealextracts were washed with water (30 mL), brine (30 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 310 mg (60%) of 73. ¹H NMR (400 MHz, CDCl₃): δ1.52 (s, 9H), 1.58 (m, 6H), 1.99 (m, 2H), 2.28 (m, 2H), 4.71 (s, 1H),6.31 (d, J=16.0 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H),7.17 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.47 (m, 2H).

Step 5:(2E)-3-{3-Chloro-4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (74)

Trifluoroacetic acid (2.0 mL) was added dropwise to 73 (300 mg, 0.706mmol) dissolved in CH₂Cl₂ (2 mL) at 0° C. The reaction mixture wasstirred at RT for 3 h and the volatiles were removed under reducedpressure. The residue was chromatographed on silica gel (20:1CH₂Cl₂:MeOH) to afford 225 mg (86%) of 74 as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.53 (br s, 6H), 1.88 (br s, 2H), 2.20 (m, 2H), 6.54(d, J=16.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.23(d, J=7.9 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H). LRMS(ESI): m/z 370 (M+H)⁺.

Example 27 (79)

Step 1: (4-Bromo-2-fluorophenyl)(4-methoxyphenyl)methanone (75)

Oxalyl chloride (4.00 mL, 45.8 mmol) was added dropwise to4-bromo-2-fluorobenzoic acid (5.1 g, 23.3 mmol) dissolved in CHCl₃ (50mL). After refluxing for 18 h, additional oxalyl chloride (4.00 mL) wasadded and refluxing was continued for 4 h. The volatiles were removedunder reduced pressure to afford 5.0 g of the crude acid chloride thatwas used without purification. AlCl₃ (10.0 g, 75.0 mmol) was addedportionwise to the crude acid chloride (5.0 g) dissolved in anisole (10mL) at 0° C. The reaction mixture was stirred at RT for 3 days and thencooled to 0° C. Water (200 mL) was cautiously added dropwise, and themixture was extracted with Et₂O (3×100 mL). The combined etherealextracts were washed with water (250 mL), brine (250 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) and recrystallization from hexanes afforded 4.1 g (57%based on 4-bromo-2-fluorobenzoic acid) of 75 as a white solid. ¹H NMR(400 MHz, CDCl₃): δ 3.87 (s, 3H), 6.94 (d, J=8.8 Hz, 2H), 7.33-7.40 (m,3H), 7.79 (d, J=8.2 Hz, 2H).

Step 2: (4-Bromo-2-fluorophenyl)(4-hydroxyphenyl)methanone (76)

A mixture of 75 (1.50 g, 5.08 mmol) and AlCl₃ (3.50 g, 26.2 mmol) wererefluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100mL) was cautiously added dropwise, and the mixture was extracted withEt₂O (3×100 mL). The combined ethereal extracts were washed with water(200 mL), brine (200 mL), and dried over MgSO₄. Concentration afforded1.39 g (97%) of 76 that was used without further purification. ¹H NMR(400 MHz, CDCl₃): δ 5.73 (br s, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.35-7.41(m, 3H), 7.77 (d, J=8.4 Hz, 2H).

Step 3: 4-[(4-bromo-2-fluorophenyl)(cyclohexylidene)methyl]phenol (77)

TiCl₄ (2.10 mL, 19.0 mmol) was added dropwise to a suspension of zincpowder (2.51 g, 38.4 mmol) in anhydrous THF (60 mL) at RT. Afterrefluxing for 1 h, a mixture of 76 (1.40 g, 4.74 mmol) and cyclohexanone(1.40 g, 14.3 mmol) dissolved in THF (20 mL) was added dropwise.Refluxing was continued for 30 min. The reaction mixture was cooled toRT and filtered through Celite. Water (250 mL) was added and the mixturewas extracted with Et₂O (3×100 mL). The combined ethereal extracts werewashed with water (200 mL), brine (200 mL), and dried over MgSO₄.Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 1.23 g (72%) of 77 as a white solid. ¹H NMR (400MHz, CDCl₃): δ 1.58 (br s, 6H), 2.05 (m, 2H), 2.25 (m, 2H), 4.68 (br s,1H), 6.73 (d, J=8.6 Hz, 2H), 6.94-7.00 (m, 3H), 7.19 (d, J=7.9 Hz, 2H).

Step 4:1,1-Dimethylethyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]-3-fluorophenyl}-2-propenoate(78)

A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL,2.55 mmol), P(OAc)₂ (15.0 mg, 0.067 mmol), P(o-tolyl)₃ (40.0 mg, 0.131mmol), and Et₃N (0.520 mL, 3.73 mmol) were heated under microwaveirradiation at 140° C. for 30 min. Water (30 mL) was added and themixture was extracted with Et₂O (3×20 mL). The combined etherealextracts were washed with water (30 mL), brine (30 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 220 mg (62%) of compound 78. ¹H NMR (400 MHz,CDCl₃): δ 1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H),4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d,J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d,J=16.0 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-3-fluorophenyl}-2-propenoicacid (79)

Trifluoroacetic acid (2.0 mL) was added dropwise to 78 (210 mg, 0.514mmol) dissolved in CH₂Cl₂ (2 mL) at 0° C. The reaction mixture wasstirred at RT for 3 h and the volatiles were removed under reducedpressure. The residue was recrystallized (EtOAc:hexanes) to afford 98.0mg (54%) of 79 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (brs, 6H), 1.98 (br s, 2H), 2.19 (br s, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.66(d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.42(d, J=7.9 Hz, 1H), 7.52 (m, 2H), 9.33 (s, 1H), 12.40 (br s, 1H). LRMS(ESI): m/z 353 (M+H)⁺.

Example 28 (85)

Step 1: 4-Bromo-N-methyl-N-(methyloxy)benzamide (80)

Pyridine (4.40 mL, 54.2 mmol) was added dropwise toN,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) dissolved inCH₂Cl₂ (100 mL) at RT. The reaction mixture was stirred for 30 min, and4-bromobenzoyl chloride (5.95 g, 27.1 mmol) dissolved in CH₂Cl₂ (50 mL)was added dropwise. The mixture was stirred for 24 h and the volatileswere removed under reduced pressure. Water (200 mL) was added and themixture was extracted with EtOAc (3×200 mL). The combined extracts werewashed successively with 5% aqueous HCl (200 mL), 5% aqueous NaHCO₃ (200mL), water (200 mL), and brine (200 mL). The mixture was dried overMgSO₄ and concentrated to afford 6.35 g (74%) of 80 as a colorless oilwhich was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ3.35 (s, 3H), 3.53 (s, 3H), 7.54 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz,2H).

Step 2: (4-Bromophenyl)(3-fluoro-4-methoxyphenyl)methanone (81)

To a stirred solution of 2-fluoro-4-bromoanisole (3.03 g, 14.8 mmol) inanhydrous THF (100 mL) was added n-butyllithium (1.6 M in hexanes, 10.2mL, 16.3 mol) dropwise at −78° C. The reaction mixture was stirred for 1h and 80 (4.02 g, 16.3 mmol) dissolved in THF (20 mL) was addeddropwise. The reaction mixture was warmed to −20° C. over 1 h, water(100 mL) was added, and the volatiles were removed under reducedpressure. The mixture was extracted with ether (3×100 mL) and thecombined extracts were washed with water (100 mL) and brine (100 mL).The mixture was dried over MgSO₄ and concentrated. The residue waschromatographed on silica gel (20:1 to 5:1 hexanes:EtOAc) to afford 2.35g (51%) of 81 as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃): δ3.97 (s, 3H), 7.01 (t, J=8.4 Hz, 1H), 7.55-7.62 (m, 6H).

Step 3: (4-Bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82)

A mixture of 81 (1.28 g, 4.34 mmol) and AlCl₃ (3.50 g, 26.2 mmol) wererefluxed in benzene (50 mL) for 3 h and cooled to RT. Water (100 mL) wascautiously added dropwise, and the mixture was extracted with ether(3×100 mL). The combined ethereal extracts were washed with water (200mL), brine (200 mL), and dried over MgSO₄. Concentration afforded 1.19 g(98%) of 82 that was used without further purification. ¹H NMR (400 MHz,CDCl₃): δ 5.80 (br s, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz,1H), 7.61-7.64 (m, 5H).

Step 4: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-2-fluorophenol (83)

Titanium tetrachloride (1.70 mL, 15.5 mmol) was added dropwise to asuspension of zinc powder (2.12 g, 32.4 mmol) in anhydrous THF (60 mL)at RT. After refluxing for 1 h, a mixture of 82 (1.18 g, 4.00 mmol) andcyclohexanone (1.18 g, 12.0 mmol) dissolved in THF (20 mL) was addeddropwise. Refluxing was continued for 30 min. The reaction mixture wascooled to RT and filtered through Celite. Water (250 mL) was added andthe mixture was extracted with ether (3×100 mL). The combined etherealextracts were washed with water (200 mL), brine (200 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 1.15 g (80%) of compound 83 as a light yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 1.58 (br s, 6H), 2.20 (m, 4H), 5.10(br s, 1H), 6.77 (m, 2H), 6.89 (t, J=8.6 Hz, 1H), 6.96 (d, J=8.4 Hz,2H), 7.39 (d, J=8.4 Hz, 2H).

Step 5:1,1-Dimethylethyl(2E)-3-{4-[cyclohexylidene(3-fluoro-4-hydroxyphenyl)-methyl]phenyl}-2-propenoate(84)

A mixture of 83 (317 mg, 0.877 mmol), tert-butyl acrylate (0.369 mL,2.55 mmol), palladium acetate (15.0 mg, 0.067 mmol), P(o-tolyl)₃ (40.0mg, 0.131 mmol), and Et₃N (0.520 mL, 3.73 mmol) were heated undermicrowave irradiation at 140° C. for 30 min. Water (30 mL) was added andthe mixture was extracted with ether (3×20 mL). The combined etherealextracts were washed with water (30 mL), brine (30 mL), and dried overMgSO₄. Concentration followed by flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 190 mg (54%) of 84. ¹H NMR (400 MHz, CDCl₃): δ1.52 (s, 9H), 1.57-1.60 (m, 6H), 2.23 (m, 4H), 5.07 (d, 1H), 6.31 (d,J=16 Hz, 1H), 6.78 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.09 (d, J=8.1 Hz,2H), 7.40 (d, J=8.1 Hz, 2H), 7.54 (d, J=16.0 Hz, 1H).

Step 6:(2E)-3-{4-[Cyclohexylidene(3-fluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (85)

Trifluoroacetic acid (2.0 mL) was added dropwise to 84 (179 mg, 0.438mmol) dissolved in CH₂Cl₂ (2 mL) at 0° C. The reaction mixture wasstirred at RT for 3 h and the volatiles were removed under reducedpressure. The residue was recrystallized (EtOAc:hexanes) to afford 120mg (78%) of 85 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (brs, 6H), 2.13 (m, 4H), 6.45 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H),6.76 (dd, J=12.3 Hz, 1.7 Hz, 1H), 6.85 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.1Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H) 9.76 (s, 1H),12.31 (br s, 1H). LRMS (ESI): m/z 353 (M+H)⁺.

Example 29 (91)

Step 1: 1-Bromo-4-(methoxymethoxy)benzene (86)

To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 mmol) inanhydrous THF (300 mL) at 0° C. was added 4-bromophenol (50.0 g, 28.9mmol) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixturewas stirred at 0° C. for 30 min, and chloromethylmethyl ether (24.8 mL,32.6 mmol) dissolved in THF (30 mL) was added dropwise over 20 min. Thereaction mixture was stirred overnight at RT. Water (250 mL) was added,and the mixture was extracted with ether (3×250 mL). The combinedethereal extracts were washed with brine, dried (MgSO₄), andconcentrated. The residue was distilled under vacuum to afford 57.6 g(92%) of 86 as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆): δ 3.33 (s,3H), 5.15 (s, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H).

Step 2: Cyclohexyl[4-(methoxymethoxy)phenyl]methanone (87)

n-Butyllithium (1.6 M in hexanes, 50.5 mL, 80.8 mmol) was added dropwiseto 86 (17.5 g, 80.8 mmol) dissolved in DME (150 mL) at −78° C. Thereaction mixture was stirred at −40° C. for 1 h, and then cannulatedinto a suspension of lithium cyclohexanes carboxylate [prepared in situby the addition of n-butyllithium (50.5 mL, 80.8 mmol) to cyclohexanescarboxylic acid (10.4 g, 80.8 mmol)] in DME (150 mL) at RT. The mixturewas stirred for 1 h, poured into ice water (300 mL), and extracted withether (3×150 mL). The combined ethereal extracts were washed with brine(300 mL) and dried over MgSO₄. Concentration followed by flashchromatography (20:1 to 5:1 hexanes:EtOAc) afforded 10.2 g (51%) of 87as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 1.18-1.57 (m, 5H), 1.72(m, 1H), 1.84 (m, 4H), 3.21 (m, 1H), 3.47 (s, 3H). 5.22 (s, 2H), 7.06(d, J=8.8 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H).

Step 3: 2-(4-Bromo-2-fluorophenyl)-1,3-dioxolane (88)

A mixture of 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol),p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) and ethyleneglycol (10 mL) were refluxed in benzene (50 mL) and EtOH (10 mL) under aDean-Stark trap for 3 h. The reaction mixture was cooled and poured intoa mixture of 5% aqueous NaHCO₃ (100 mL) and ice (100 mL). The mixturewas extracted with ether (3×150 mL), and the combined ethereal extractswere washed with brine (200 mL) and dried (MgSO₄). Concentration underreduced pressure afforded 6.02 g (99%) of 88 that was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): δ 4.01-4.14 (m, 4H), 6.02(s, 1H), 7.24-7.31 (m, 2H), 7.41 (t, J=7.9 Hz, 1H).

Step 4: 4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-2-fluorobenzaldehyde(89)

n-Butyllithium (1.6 M in hexanes, 1.33 mL, 2.13 mmol) was added dropwiseto 88 (503 mg, 2.04 mmol) dissolved in anhydrous THF (25 mL) at −78° C.The reaction mixture was stirred for 20 min and 87 (460 mg, 1.85 mmol),dissolved in THF (25 mL), was added dropwise. The mixture was warmedslowly to RT and stirred overnight. Water (150 mL) was added and themixture was extracted with ether (3×100 mL). The combined etherealextracts were washed with water (200 mL), brine (200 mL), dried (MgSO₄),and concentrated under reduced pressure. The resulting crude oil wastaken up in a mixture of EtOH (10 mL) and 12 M HCl (2 mL) and refluxedfor 2 h. Removal of solvent and flash chromatography (20:1 to 5:1hexanes:EtOAc) afforded 200 mg (35%) of 89 as a white solid. ¹H NMR (400MHz, CDCl₃): δ 1.60 (br s, 6H), 2.23 (m, 4H), 6.00 (s, 1H), 6.79 (d,J=8.2 Hz, 2H), 6.89-6.95 (m, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.6Hz, 1H), 10.28 (s, 1H).

Step 5: tert-Butyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}prop-2-enoate(90)

A solution of (tert-butoxycarbonylmethylene)triphenylphosphorane (610mg, 1.62 mmol) in CH₂Cl₂ (10 mL) was added dropwise to 89 (200 mg, 0.644mmol) dissolved in CH₂Cl₂ (10 mL) at RT. After stirring for 2 h at RT,water (50 mL) was added and the mixture was extracted with CH₂Cl₂ (3×25mL). The combined organic layers were washed with brine (50 mL) anddried over MgSO₄. Concentration followed by flash chromatography (20:1to 5:1 hexanes:EtOAc) and recrystallization (hexanes:EtOAc) afforded 180mg (68%) of 90 as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃): δ1.52 (s, 9H), 1.59 (br s, 6H), 2.22 (br s, 4H), 5.24 (s, 1H), 6.40 (d,J=16.3 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.80-6.89 (m, 2H), 6.94 (d,J=8.4 Hz, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.67 (d, J=16.3 Hz, 1H).

Step 6:(2E)-3-{4-[Cyclohexylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoicacid (91)

Trifluoroacetic acid (1.5 mL) was added dropwise to 90 (180 mg, 0.551mmol) dissolved in CH₂Cl₂ (3 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h and the volatiles were removed under reducedpressure. Water (30 mL) was added and the mixture was extracted withEtOAc (3×20 mL). The combined organic layers were washed with water (30mL), brine (30), and dried over MgSO₄. Concentration followed byrecrystallization (EtOAc) afforded 99 mg (64%) of 91 as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (br s, 6H), 2.13 (br s, 4H),6.51 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.85-6.91 (m, 4H), 7.59(d, J=16.0 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H), 9.36 (s, 1H), 12.51 (br s,1H). LRMS (APCI): m/z 353 (M+H)⁺.

Example 30 (94)

Step 1: [4-(Methyloxy)phenyl][4-(methylsulfonyl)phenyl]methanone (92)

4-(Methylsulfonyl)benzoic acid (0.5 g, 2.42 mmol) was suspended inCH₂Cl₂ (15 mL). Oxalyl chloride (0.44 mL, 4.85 mmol) was added dropwise,followed by addition of two drops of DMF. The reaction mixture wasstirred at room temperature for 3 h. CH₂Cl₂ and the excess of oxalylchloride were removed under vacuum. The residue was dissolved inCH₂Cl₂(10 mL) with anisole (0.54 mL, 4.84 mmol). Cooled in an ice bath,aluminum chloride (0.49 g, 3.63 mmol) was added in portions. The mixturewas stirred at 0° C. for 2 h, then heated at reflux overnight. Cooled toroom temperature, the mixture was poured into 1 N HCl (15 mL) with ice,the pinkish solid was collected and washed with water, hexanes and driedto give 0.50 g (71%) of the title compound (92) as light pink solid. ¹HNMR (400 MHz, DMSO-d₆): δ 3.28 (s, 3H), 3.85 (s, 3H), 7.09 (d, J=8.8 Hz,2H), 7.76 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 8.07 (d, J=8.2 Hz,2H). LCMS (ESI): m/z 291 (M+H)⁺.

Step 2: (4-Hydroxyphenyl)[4-(methylsulfonyl)phenyl]methanone (93)

A mixture of [4-(Methyloxy)phenyl][4-(methylsulfonyl)phenyl]methanone(92) (0.20 g, 0.69 mmol) and aluminum chloride (0.38 g, 2.76 mmol) wererefluxed in benzene (10 mL) for 2 h and then cooled to 0° C. in an icebath. Water (10 mL) was added slowly, and the mixture was extracted withEtOAc (2×75 mL). The combined organic extract washed with water, brine,and dried over Na₂SO₄. Concentration of the extract gave the titlecompound (93) as light brown solid (0.19 g, 100%), which was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 3.28 (s, 3H),6.89 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H),8.05 (d, J=8.2 Hz, 2H), 10.56 (s, 1H). LCMS (ES): m/z 277 (M+H)⁺, m/z275 (M−H)⁻.

Step 3: 4-[[4-(Methylsulfonyl)phenyl](3,3,5,5tetramethylcyclohexylidene)methyl]phenol (94)

To a stirred suspension of zinc powder (0.36 g, 5.50 mmol) in THF (15mL) was slowly added TiCl₄ (0.30 mL, 2.75 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of (4-hydroxyphenyl)[4-(methylsulfonyl)phenyl]methanone (93) (0.19 g, 0.69 mmol) and3,3,5,5-tetramethyl cyclohexanone (0.33 g, 2.06 mmol) in THF (4 mL) wasadded to the mixture. The reaction mixture was heated at reflux withstirring under a nitrogen atmosphere for 1.5 h. The reaction mixture wasallowed to cool at room temperature. To the reaction mixture was slowlyadded 10% aqueous K₂CO₃ (15 mL). The reaction mixture was filteredthrough a pad of celite and the pad washed with ethyl acetate (70 mL).The filtrate was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was further extracted with ethyl acetate(25 mL). The combined organic phase washed with water, brine, dried overNa₂SO₄, filtered, and the filtrate was concentrated to give the crudeproduct as yellow oil. The crude product was purified by chromatographyon a silica gel column eluted with a gradient from hexanes to 25%EtOAc:hexanes to give white foam residue, which was triturated with hothexanes (containing 1% MeOH) to afford 0.21 g (76%) of the titlecompound (94) as white solid, m.p. 149-150° C. ¹H NMR (300 MHz,DMSO-d₆): δ 0.90 (s, 6H), 0.91 (s, 6H), 1.28 (s, 2H), 1.88 (s, 2H), 1.95(s, 2H), 3.20 (s, 3H), 6.70 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H),7.40 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 9.34 (s, 1H). LCMS (ES):m/z 397 (M−H)⁻.

Example 31 (95)

Step 1:4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzamide(95)

To a cold (−15° C.) solution of4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoicacid (0.100 g, 0.274 mmol) (26) in THF were added Et₃N (0.042 mL, 0.302mmol) and ethyl chloroformate (0.029 mL, 0.302 mmol) sequentially. Theresultant solution was stirred at that temperature for 0.5 h. An aqueous28% NH₄OH solution was added slowly to the above mixture at −15° C. andstirred the resultant mixture at room temperature for 15 h. Reactionmixture was poured into sat. NH₄Cl solution (30 mL) and then extractedwith EtOAc (2×40 mL). The combined organic layer washed with brine (1×25mL), dried (Na₂SO₄), and concentrated under reduced pressure to affordthe crude product. The product was purified by SiO₂ columnchromatography using CHCl₃ and MeOH (100:00 to 9:1) as an eluent toafford 0.035 g (35%) of the title compound (95) as white crystallinesolid. Around 25 mg of starting material was also recovered from thisreaction. mp 209° C.-210° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.29 (s, 1H),7.87 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.27 (s, 1H), 7.15 (d, J=8.0 Hz,2H), 6.92 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 1.91 (s, 2H), 1.85(s, 2H), 1.24 (s, 2H), 0.87 (s, 6H), 0.85 (s, 6H). LCMS (ESI): m/z362.31 (M−H)⁻.

Example 32 (97)

Step 1: {4-[(2-Hydroxyethyl)oxy]phenyl}(4-hydroxyphenyl)methanone (96)

To a solution of 4,4′-dihydroxybenzophenone (3.0 g, 13.9 mmol) in DMF(30 mL) was added Cs₂CO₃ (13.55 g, 41.6 mmol). The mixture was heated at80° C. under nitrogen for 1 h. Cooled to room temperature, NaI (2.08 g,13.9 mmol) was added, followed by dropwise addition of a solution of2-chloroethanol (1.03 mL, 15.3 mmol) in DMF (7 mL) with stirring. Thereaction mixture was heated at 80° C. under nitrogen overnight. Themixture was cooled to room temperature and quenched with saturatedaqueous NH₄Cl (100 mL), then extracted with EtOAc (3×60 mL). The organiclayers were combined and washed with water, brine and dried over Na₂SO₄.Concentration gave a reddish brown oil which was further purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 80% EtOAc:hexanes yielded a pale white solid. Triturationwith 10% EtOAc:hexanes afforded 1.30 g (36%) of 96 as a white solid. mp146-147° C. ¹H NMR (400 MHz, CD₃OD): δ 3.85-3.95 (m, 2H), 4.10-4.20 (m,2H), 6.87 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.6 Hz,2H), 7.73 (d, J=8.8 Hz, 2H). LRMS (ESI): m/z 259 (M+H)⁺, 257 (M−H)⁻.

Step 2:4-[{4-[(2-Hydroxyethyl)oxy]phenyl}(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(97)

To a stirred suspension of Zn (0.50 g, 7.59 mmol) in THF (10 mL) wasadded TiCl₄ (0.42 mL, 3.79 mmol) dropwise. The mixture was refluxedunder nitrogen for 2.5 h. Cooled to room temperature, a solution of 96(0.245 g, 0.95 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.45 g, 2.85mmol) in THF (15 mL) was added at once. The reaction mixture wasrefluxed for another 2.5 h. Cooled to room temperature, the reaction wasquenched with 10% K₂CO₃ (20 mL). The quenched reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc (100 mL).The filtrate was transferred to a separatory funnel, the layers wereseparated and the aqueous phase was extracted with EtOAc (50 mL). Theorganic extracts were combined, washed with brine and dried (Na₂SO₄).Concentration yielded a pale brown oil which was further purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 45% EtOAc:hexanes to give a light yellow solid,Crystallization from 7:1 hexanes:EtOAc yielded 97 as colorless needles(0.15 g, 42%). mp 154-155° C. ¹H NMR (400 MHz, CD₃OD): δ 0.91 (s, 6H),0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.80-3.90 (m,2H), 4.00-4.10 (m, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (ESI): m/z 381(M+H)⁺, 379 (M−H)⁻. The sample was silated prior to EI analysis. HRMS(EI) Calcd for C₃₁H₄₈O₃Si₂: 524.3142 (M⁺). Found: 524.3128.

Example 33 (98)

Step 1:4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylcarboxylicacid (98)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenol(14) (0.102 g, 0.255 mmol), 3-carboxyphenylboronic acid (0.085 g, 0.51mmol, 2 eq), tetrakis(triphenylphosphine)palladium (0) (0.020 g, 0.017mmol, 0.07 eq), aqueous Na₂CO₃ (2 M, 8 mL), and ethylene glycol dimethylether (5 mL). The stirred reaction mixture was heated at refluxovernight under a nitrogen atmosphere. The reaction mixture was allowedto cool to room temperature and transferred to a separatory funnel. Thereaction mixture was partitioned between 1 N HCl (aqueous) and CH₂Cl₂.The layers were separated and the organic phase washed with brine, driedover MgSO₄, filtered, and the filtrate was concentrated to give an oil.The crude product was purified by reverse phase preparative HPLC using aC18 column and a CH₃CN:H₂O (50:50 to 100:0) gradient with 0.05% TFA as amodifier to give 0.052 g (46%) of compound 98 as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H), 6.67(d, J=8.4 Hz, 2 H), 6.95 (d, J=8.5 Hz, 2 H), 7.22 (d, J=8.0 Hz, 2 H),7.55 (t, J=7.7 Hz, 1 H), 7.61 (d, J=8.3 Hz, 2 H), 7.89 (dd, J=7.8, 1.6Hz, 2 H), 8.14 (s, 1 H), 9.28 (s, 1 H), 13.04 (s, 1 H). HRMS (ESI) Calcdfor C₃₀H₃₃O₃: 441.2430 (M+H)⁺. Found: 441.2419.

Example 34 (99)

Step 1:N-{4′-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-biphenyl-4-yl}-acetamide(99)

To a solution of4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.1 g, 0.250 mmol) and (4-acetylaminophenyl)boronic acid (0.148, 0.826mmol) in ethylene glycol dimethyl ether (8 mL) was addedtetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmol) followedby 2 M Na₂CO₃ (3 mL). The reaction mixture was refluxed for 4 h, cooledto room temperature then diluted with water followed by EtOAc. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with water followed by brine,dried (MgSO₄) filtered and concentrated to an oil. The crude oil wasdissolved in DCM, loaded onto silica gel and purified with a gradient of100% hexanes to 40% hexanes:EtOAc over 60 mins. Pure fractions werecombined and concentrated to give 0.05 g (41%) of the title compound 99as an off white powder. ¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12 H),1.25 (s, 2 H), 1.93 (s, 4 H), 2.03 (s, 3 H), 6.66 (d, J=8.5 Hz, 2 H),6.94 (d, J=8.4 Hz, 2 H), 7.16 (d, J=8.3 Hz, 2 H) 7.52-7.64 (m, 6 H),9.27 (s, 1 H), 9.99 (s, 1 H). HRMS (ESI) Calcd for C₃₁H₃₆NO₂: 454.2746(M+H)⁺. Found 454.2757.

Example 35 (100)

Step 1:N-{4′-[(4-Hydroxy-phenyl)-(3,3,5-5-tetramethyl-cyclohexylidene)-methyl]-biphenyl-4-yl}-methanesulfonamide(100)

The title compound was prepared using the conditions described inExample 97 using4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.1 g, 0.250 mmol), [(4-methylsulfonyl)aminophenyl]boronic acid (0.178,0.826 mmol), ethylene glycol dimethyl ether (8 ml),tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmol) and 2 MNa₂CO₃ (3 mL) to afford 0.070 g (57%) of compound 100 as a powder. ¹HNMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.25 (s, 2 H), 1.93 (s, 4 H),2.99 (s, 3 H), 6.66 (d, J=8.4 Hz, 2 H), 6.94 (d, J=8.4 Hz, 2 H), 7.17(d, J=8.3 Hz, 2 H) 7.25 (d, J=8.6 Hz, 2 H), 7.54 (d, J=8.2 Hz, 2 H),7.61 (d, J=8.5 Hz, 2 H), 9.28 (s, 1 H), 9.82 (s, 1 H). HRMS (ESI) Calcdfor C₃₀H₃₄NO₃S: 488.2259 (M−H)⁻. Found 488.2265

Example 36 (102)

Step 1: methyl4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoate(101)

The general McMurry protocol, described for 14 was followed. Thus,methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.196 g, 0.765 mmol)and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.370 g, 2.37mmol) were subjected for McMurry coupling reaction conditions. Standardwork-up followed by purification by column chromatography gave 0.272 g(93%) of the title compound 101 as a white foam. ¹H NMR (300 MHz,CDCl₃): δ 7.98 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 3.92 (s, 3H), 2.27 (s, 2H), 2.21 (s,2H), 1.28 (s, 6H), 1.25 (s, 6H). LCMS (ESI): m/z 379 (M−H)⁻.

Step 2:4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoicacid (102)

The hydrolysis procedure described for 191 was employed. Thus, methyl4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoate(101) (0.212 g, 0.557 mmol) in THF/EtOH (1:1, 6 mL) was treated with 1 NNaOH (3 mL, excess). Standard work-up followed by purification gave0.170 g (83%) of compound 102 as a white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 12.77 (br s, 1H), 9.40 (br s, 1H), 7.88 (d, J=8.1 Hz, 2H),7.27 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H),2.18 (s, 2H), 2.11 (s, 2H), 1.14 (s, 6H), 1.12 (s, 6H). LCMS (ESI): m/z365 (M−H)⁻.

Example 37 (103)

Step 1:4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenylcarboxylicacid (103)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenol(14) (0.105 g, 0.26 mmol), 4-dihydroxyborane-benzoic acid (0.093 g, 0.56mmol, 2.2 eq), tetrakis(triphenylphosphine)palladium (0) (0.023 g, 0.02mmol, 0.08 eq), aqueous Na₂CO₃ (2 M, 3 mL), and ethylene glycol dimethylether (5 mL). The reaction mixture was heated overnight at reflux withstirring under a nitrogen atmosphere. The reaction mixture was allowedto stand at RT under nitrogen for six days. To the reaction mixture wereadded 4-dihydroxyborane-benzoic acid (0.099 g, 0.60 mmol, 2.3 eq),tetrakis(triphenylphosphine)palladium (0) (0.031 g, 0.027 mmol, 0.10eq), aqueous sodium carbonate (2 M, 2 mL), and ethylene glycol dimethylether (2 mL). The stirred reaction mixture was heated overnight atreflux under nitrogen. The reaction mixture was allowed to stand at RTunder nitrogen for one week. The reaction mixture was partitionedbetween 1 N HCl (aqueous) and CH₂Cl₂. The organic phase was separated,washed with brine, dried over MgSO₄, filtered, and the filtrate wasconcentrated to give the crude product as an oil. The crude product waspartially purified by flash chromatography on silica gel with aCH₂Cl₂:MeOH (100:0 to 96:4) gradient to give 0.052 g of the impureproduct as a an oil. The impure product was purified by reverse phasepreparative HPLC using a C18 column and an CH₃CN:H₂O (75:25 to 100:0)gradient with 0.05% TFA as a modifier to give 9.3 mg (8%) of compound103 as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (br s, 12H), 1.26 (br s, 2 H), 1.93 (br s, 4 H), 6.67 (d, J=8.5 Hz, 2 H), 6.96(d, J=8.4 Hz, 2 H), 7.23 (d, J=8.1 Hz, 2 H), 7.65 (d, J=8.1 Hz, 2 H),7.77 (d, J=8.2 Hz, 2 H), 7.98 (d, J=8.4 Hz, 2 H), 9.29 (s, 1 H), 12.94(br s, 1 H).

Example 38 (108)

Step 1: (4-Bromophenyl)[3-chloro-4-(methyloxy)phenyl]methanone (104)

The title compound 104 (1.25 g, 84%) was obtained in a similar mannerpreviously reported for 27. ¹H NMR (400 MHz, CDCl₃): δ 3.98 (s, 3H),6.99 (d, J=8.6 Hz, 1H), 7.62 (m, 4H), 7.71 (dd, J=2.1 Hz, 8.5 Hz, 1H),7.85 (d, J=2.01 Hz, 1H).

Step 2: (4-Bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105)

The title compound 105 (1.06 g, 88%) was obtained in a similar mannerpreviously reported for 28. ¹H NMR (400 MHz, DMSO-d₆): δ 7.08 (d, J=8.4Hz, 1H), 7.56 (dd, J=2.1 Hz, 8.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.70(d, J=2.0 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 11.31 (s, 1H).

Step 3: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-2-chlorophenol (106)

The title compound was prepared according to the procedure described for29, with modification. Upon cooling, the reaction mixture was quenchedwith 10% aqueous K₂CO₃ and filtered through a pad of Celite. The padwashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product.The crude product was purified by chromatography on silica gel withEtOAc:hexanes to afford 0.48 g (79%) of compound 106. ¹H NMR (400 MHz,CDCl₃): δ 1.57 (m, 6H), 2.17-2.23 (m, 4H), 5.45 (s, 1H), 6.91 (d, J=2.2Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.02 (m, 1H), 7.39 (d, J=8.4 Hz, 2H).

Step 4:Ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cyclohexylidene)methyl]phenyl}-2-propenoate(107)

The title compound 107 (187 mg, 58%) was obtained in a similar mannerpreviously reported for 30. ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.1Hz, 3H), 1.60 (br s, 6H), 2.22 (m, 4H), 4.25 (q, J=7.1 Hz, 2H), 6.39 (d,J=15.9 Hz, 1H), 6.92 (s, 2H), 7.04 (s, 1H), 7.10 (d, J=8.1 Hz, 2H), 7.43(d, J=8.1 Hz, 2H), 7.65 (d, J=16.1 Hz, 1H).

Step 5:(2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(cyclohexylidene)methyl]phenyl}-2-propenoicacid (108)

The title compound 108 (0.14 g, 82%) was obtained in a similar mannerpreviously reported for 31. ¹H NMR (DMSO-d₆): δ 1.53 (br s, 6H),2.12-2.14 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.82-6.89 (m, 2H), 6.94 (m,1H), 7.07 (d, J=8.1 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.1 Hz,2H), 10.11 (s, 1H), 12.32 (s, 1H). LRMS (ESI): m/z, 369 (M+H)⁺.

Example 39 (113)

Step 1: (4-Bromophenyl)[2-fluoro-4-(methyloxy)phenyl]methanone (109)

The title compound (0.38 g, 26%) was obtained in a similar mannerpreviously reported for 27. ¹H NMR (400 MHz, CDCl₃): δ 3.87 (s, 3H),6.65 (dd, J=2.4 Hz, 11.9 Hz, 1H), 6.79 (dd, J=2.3 Hz, 8.7 Hz, 1H), 7.57(t, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H).

Step 2: (4-Bromophenyl)(2-fluoro-4-hydroxyphenyl)methanone (110)

The title compound (0.31 g, 86%) was obtained in a similar mannerpreviously reported for 28. ¹H NMR (400 MHz, DMSO-d₆): δ 6.64 (dd, J=2.1Hz, 12.5 Hz, 1H), 6.73 (dd, J=2.1 Hz, 8.5 Hz, 1H), 7.45 (t, J=8.6 Hz,1H), 7.61 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 10.79 (s, 1H).

Step 3: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-3-fluorophenol (111)

The title compound was prepared according to the procedure described for29, with modification. Upon cooling, the reaction mixture was quenchedwith 10% aqueous K₂CO₃ and filtered through a pad of Celite. The padwashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product.The crude product was purified by chromatography on silica gel withEtOAc:hexanes to give 0.32 g (86%) of compound 111. ¹H NMR (400 MHz,CDCl₃): δ 1.57 (s, 6H), 2.07 (m, 2H), 2.23 (m, 2H), 4.90 (s, 1H),6.51-6.55 (m, 2H), 6.91 (t, J=8.5 Hz, 1H), 7.00 (d, J=8.2 Hz, 2H), 7.38(d, J=8.5 Hz, 2H).

Step 4:Ethyl(2E)-3-{4-[cyclohexylidene(2-fluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoate(112)

The title compound (0.22 g, 65%) was obtained in a similar mannerpreviously reported for 30. ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.1Hz, 3H), 1.59 (s, 6H), 2.10 (m, 2H), 2.25 (m, 2H), 1.97 (q, J=7.1 Hz,2H), 6.37 (d, J=15.9 Hz, 1H), 6.51-6.55 (m, 2H), 6.92 (t, J=8.5 Hz, 1H),7.15 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.64 (d, J=15.9 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(2-fluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (113)

The title compound (0.17 g, 86%) was obtained in a similar mannerpreviously reported for 31. ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (s, 6H),2.02 (m, 2H), 2.17 (m, 2H), 6.44 (d, J=16.1 Hz, 1H), 6.48 (dd, J=2.2 Hz,11.5 Hz, 1H), 6.54 (dd, J=2.2 Hz, 8.2 Hz, 1H), 6.89 (t, J=8.7 Hz, 1H),7.07 (d, J=8.1 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H),9.8 (s, 1H), 12.32 (s, 1H). LCMS (ESI): m/z 385 (M+Na)⁺.

Example 40 (118)

Step 1: (4-Bromophenyl)[2,3-dimethyl-4-(methyloxy)phenyl]methanone (114)

The title compound (1.46 g, 92%) was obtained in a similar mannerpreviously reported for 27. ¹H NMR (400 MHz, CDCl₃): δ 2.19 (s, 3H),2.23 (s, 3H), 3.87 (s, 3H), 6.72 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.6 Hz,1H), 7.57 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H).

Step 2: (4-Bromophenyl)(4-hydroxy-2,3-dimethylphenyl)methanone (115)

The title compound (1.16 g, 83%) was obtained in a similar mannerpreviously reported for 28. ¹H NMR (400 MHz, DMSO-d₆): δ 2.08 (s, 3H),2.11 (s, 3H), 6.71 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.57 (d,J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 9.94 (s, 1H).

Step 3: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-2,3-dimethylphenol(116)

The title compound was prepared according to the procedure described for29, with modification. Upon cooling, the reaction mixture was quenchedwith 10% aqueous K₂CO₃ and filtered through a pad of Celite. The padwashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product.The crude product was purified by chromatography on silica gel withEtOAc:hexanes to give 0.53 g (87%) of compound 116. ¹H NMR (400 MHz,CDCl₃): δ 1.59 (m, 6H), 1.97 (m, 2H), 2.06 (s, 3H), 2.13 (s, 3H), 2.29(m, 2H), 4.60 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H),6.99 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H).

Step 4:Ethyl(2E)-3-{4-[cyclohexylidene(4-hydroxy-2,3-dimethylphenyl)methyl]phenyl}-2-propenoate(117)

The title compound 117 (0.15 g, 49%) was obtained in a similar mannerpreviously reported for 30. ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.1Hz, 3H), 1.59 (m, 6H), 1.98 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.32(m, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.70 (s, 1H), 6.36 (d, J=15.9 Hz, 1H),6.60 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H),7.39 (d, J=8.1 Hz, 2H), 7.63 (d, J=15.9 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(4-hydroxy-2,3-dimethylphenyl)methyl]phenyl}-2-propenoicacid (118)

The title compound 118 (0.14 g, 100%) was obtained in a similar mannerpreviously reported for 31. ¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (m, 6H),1.90 (m, 2H), 1.96 (s, 3H), 1.99 (s, 3H), 2.23 (m, 2H), 6.42 (d, J=16.1Hz, 1H), 6.59 (d, J=8.2 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.1Hz, 2H), 7.50 (d, J=15.9 Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 9.05 (s, 1H),12.31 (s, 1H). LCMS (ESI): m/z 363 (M+H)⁺.

Example 41 (123)

Step 1: (4-Bromophenyl)[2,3-difluoro-4-(methyloxy)phenyl]methanone (119)

The title compound 119 (0.94 g, 66%) was obtained in a similar mannerpreviously reported for 27. ¹H NMR (400 MHz, CDCl₃): δ 3.98 (s, 3H),6.84 (m, 1H), 7.35 (m, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.5 Hz,2H).

Step 2: (4-Bromophenyl)(2,3-difluoro-4-hydroxyphenyl)methanone (120)

The title compound 120 (0.76 g, 84%) was obtained in a similar mannerpreviously reported for 28. ¹H NMR (400 MHz, CDCl₃): 5.75 (s, 1H), 6.90(m, 1H), 7.31 (m, 1H), 7.61-7.67 (m, 4H).

Step 3: 4-[(4-Bromophenyl)(cyclohexylidene)methyl]-2,3-difluorophenol(121)

The title compound was prepared according to the procedure described for29, with modification. Upon cooling, the reaction mixture was quenchedwith 10% aqueous K₂CO₃ and filtered through a pad of Celite. The padwashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to give the crude product.The crude product was purified by chromatography on silica gel withEtOAc:hexanes to give 0.77 g (85%) of compound 121. ¹H NMR (400 MHz,CDCl₃): δ 1.58 (m, 6H), 2.06 (m, 2H), 2.22 (m, 2H), 5.80 (s, 1H), 6.69(d, J=5.1 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H).

Step 4:Ethyl(2E)-3-{4-[cyclohexylidene(2,3-difluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoate(122)

The title compound 122 (0.22 g, 70%) was obtained in a similar mannerpreviously reported for 30. ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.1Hz, 3H), 1.59 (m, 6H), 2.10 (m, 2H), 2.25 (m, 2H), 4.25 (q, J=7.1 Hz,2H), 6.38 (d, J=15.9 Hz, 1H), 6.70 (d, J=5.1 Hz, 2H), 7.14 (d, J=8.1 Hz,2H), 7.42 (d, J=8.1 Hz, 2H), 7.64 (d, J=15.9 Hz, 1H).

Step 5:(2E)-3-{4-[Cyclohexylidene(2,3-difluoro-4-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (123)

The title compound 123 (0.196 g, 98%) was obtained in a similar mannerpreviously reported for 31. ¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (m, 6H),2.03 (m, 2H), 2.19 (m, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.71 (d, J=5.3 Hz,2H), 7.09 (d, J=8.1 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.2 Hz,2H), 10.31 (s, 1H), 12.35 (s, 1H). LCMS (ESI): m/z 393 (M+Na).

Example 42 (126)

Step 1: 4-[(4-Bromophenyl)(cycloheptylidene)methyl]-2-chlorophenol (124)

To a stirred suspension of zinc powder (1.35 g, 20.5 mmol) in THF (40mL) was slowly added TiCl₄ (1.13 mL, 10.3 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.80 g, 2.57mmol) and cycloheptanone (0.89 g, 7.70 mmol) in THF (15 mL) was added tothe mixture. The reaction mixture was heated at reflux with stirringunder a nitrogen atmosphere for 1.5 h. The reaction mixture was allowedto cool to room temperature. To the reaction mixture was slowly added10% aqueous K₂CO₃ (40 mL). The reaction mixture was filtered through apad of Celite and the pad washed with EtOAc (100 mL). The filtrate wastransferred to a separatory funnel and the layers were separated. Theaqueous layer was further extracted with EtOAc (50 mL). The combinedorganic phase washed with brine, dried over Na₂SO₄, filtered, and thefiltrate was concentrated to give the crude product as brown oil. Thecrude product was purified by flash chromatography on silica gel withhexanes:EtOAc (20:1) to give 0.64 g (64%) of compound 124 as a yellowviscous oil. ¹H NMR (400 MHz, DMSO-d₆): δ 1.50 (br s, 8H), 2.10-2.25 (m,4H), 6.85-6.92 (m, 2H), 7.02 (br s, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.47(d, J=8.4 Hz, 2H), 10.1 (s, 1H). LCMS (APCI): m/z 413 (M+Na)⁺.

Step 2:Ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate(125)

To a round-bottomed flask were added4-[(4-bromophenyl)(cycloheptylidene)methyl]-2-chlorophenol (124) (0.32g, 0.82 mmol), ethyl acrylate (0.90 mL, 8.17 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.08 mmol),triethylamine (0.60 mL, 4.08 mmol) and DMF (10 mL). The stirred reactionmixture was heated overnight at 100° C. under a nitrogen atmosphere. Thereaction mixture was allowed to cool to room temperature and transferredto a separatory funnel with the aid of water and EtOAc (100 mL). Thelayers were separated and the organic phase washed with water, brine,dried over Na₂SO₄, filtered, and the filtrate was concentrated to givereddish brown oil. The crude product was purified by chromatography on asilica gel column eluted with a gradient from hexanes to 15%EtOAc:hexanes to give 0.23 g (69%) of compound 125 as a colorlessviscous oil. ¹H NMR (400 MHz, CDCl₃): δ 1.33 (t, J=7.1 Hz, 3H), 1.58 (brs, 8H), 2.30 (br s, 4H), 4.25 (q, J=7.1 Hz, 2H), 5.42 (s, 1H), 6.39 (d,J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.10 (d, J=1.8 Hz, 1H), 7.14 (d,J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H). LCMS(ESI): m/z, 433 (M+Na)⁺, 409 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoicacid (126)

To a solution ofethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate(125) (0.23 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) wasadded an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with anaqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50mL). The combined organic extract washed with brine and dried overNa₂SO₄. Upon concentration, light brown foam was obtained. Triturationwith hexanes (containing 1% MeOH) afforded compound 126 as a white solid(0.175 g, 82%). mp 155-156° C. ¹H NMR (400 MHz, DMSO-d₆): δ 1.51 (br s,8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.02(s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.58 (d, J=7.8Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 383 (M+H)⁺, m/z381 (M−H)⁻. Anal. Calcd for C₂₃H₂₃ClO₃.0.25H₂O: C, 71.31; H, 6.11;Found: C, 71.26; H, 6.05.

Example 43 (129)

Step 1:4-[(4-Bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-chlorophenol(127)

To a stirred suspension of zinc powder (0.59 g, 8.99 mmol) in THF (20mL) was slowly added TiCl₄ (0.50 mL, 4.50 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.35 g, 1.12mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.53 g, 3.37 mmol) in THF(6 mL) was added to the mixture. The reaction mixture was heated atreflux with stirring under a nitrogen atmosphere for 1.5 h. The reactionmixture was allowed to cool to room temperature. To the reaction mixturewas slowly added 10% aqueous K₂CO₃ (20 mL). The reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc (50 mL).The filtrate was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was further extracted with EtOAc (25 mL).The combined organic phase washed with brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asbrown oil. The crude product was purified by flash chromatography onsilica gel with hexanes:EtOAc (30:1) to give 0.38 g (78%) of 127 as alight yellow viscous oil. ¹H NMR (400 MHz, CDCl₃): δ 0.91 (s, 6H), 0.93(s, 6H), 1.29 (s, 2H), 1.92 (s, 2H), 1.95 (s, 2H), 5.42 (s, 1H),6.88-6.98 (m, 2H), 7.01 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 7.39 (d, J=8.2Hz, 2H). LCMS (ESI): m/z 431 (M−H)⁻.

Step 2: Ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (128)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-chlorophenol (127) (0.38 g, 0.88 mmol), ethylacrylate (0.96 mL, 8.80 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.062 g, 0.09 mmol), Et₃N(0.61 mL, 4.38 mmol) and DMF (10 mL). The stirred reaction mixture washeated overnight at 100° C. under a nitrogen atmosphere. The reactionmixture was allowed to cool to room temperature and transferred to aseparatory funnel with the aid of water and EtOAc (100 mL). The layerswere separated and the organic phase washed with water, brine, dried(Na₂SO₄), filtered, and the filtrate was concentrated to give reddishbrown oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 15% EtOAc:hexanes togive 0.26 g (66%) of compound 128 as a yellow viscous oil. ¹H NMR (400MHz, CDCl₃): δ 0.92 (s, 6H), 0.94 (s, 6H), 1.30 (s, 2H), 1.33 (t, J=7.1Hz, 3H), 1.96 (s, 2H), 1.97 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 5.43 (s,1H), 6.39 (d, J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.11 (d, J=1.8 Hz, 1H),7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H).LCMS (ESI): m/z, 453 (M+H)⁺, 451 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoicacid (129)

To a solution ofethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (128) (0.26 g, 0.57 mmol) ina mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Uponcooling, the mixture was acidified to pH=2 with an aqueous solution of 2N HCl. The mixture was extracted with EtOAc (2×50 mL). The combinedorganic extract washed with brine and dried over Na₂SO₄. Uponconcentration and adding hexanes, the title compound 129 was obtained aslight yellow foam (0.24 g, 99%). mp 111-114° C. ¹H NMR (400 MHz,DMSO-d₆): δ 0.86 (s, 6H), 0.88 (s, 6H), 1.25 (s, 2H), 1.87 (s, 2H), 1.90(s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.06 (s, 1H), 7.16(d, J=7.7 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59 (d, J=7.5 Hz, 2H),10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 423 (M−H)⁻. Anal. Calcdfor C₂₆H₂₉ClO₃: C, 73.48; H, 6.88; Found: C, 73.18; H, 7.06.

Example 44 (132)

Step 1:4-[(4-Bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-chlorophenol(130)

To a stirred suspension of zinc powder (0.59 g, 8.99 mmol) in THF (20mL) was slowly added TiCl₄ (0.50 mL, 4.50 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.35 g, 1.12mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.54 g, 3.37mmol) in THF (6 mL) was added to the mixture. The reaction mixture washeated at reflux with stirring under a nitrogen atmosphere for 1.5 h.The reaction mixture was allowed to cool to room temperature. To thereaction mixture was slowly added 10% aqueous K₂CO₃ (20 mL). Thereaction mixture was filtered through a pad of Celite and the pad waswashed with EtOAc (100 mL). The filtrate was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was furtherextracted with EtOAc (25 mL). The combined organic phase washed withbrine, dried over Na₂SO₄, filtered, and the filtrate was concentrated togive the crude product as yellow viscous oil. The crude product waspurified by chromatography on a silica gel column eluted with a gradientfrom hexanes to 15% EtOAc:hexanes to give 0.47 g (96%) of compound 130as a yellow viscous oil. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 6H), 1.22(s, 6H), 2.18 (s, 2H), 2.22 (s, 2H), 5.47 (s, 1H), 6.90-7.00 (m, 2H),7.02 (d, J=8.4 Hz, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H).LCMS (ESI), m/z 433 (M−H)⁻.

Step 2:Ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate(131)

To a round-bottomed flask were added4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-chlorophenol(130) (0.47 g, 1.08 mmol), ethyl acrylate (1.20 mL, 10.8 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.076 g, 0.11 mmol), Et₃N(0.75 mL, 5.39 mmol) and DMF (12 mL). The stirred reaction mixture washeated overnight at 100° C. under a nitrogen atmosphere. The reactionmixture was allowed to cool to room temperature and transferred to aseparatory funnel with the aid of water and EtOAc (100 mL). The layerswere separated and the organic phase washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated to give brownoil. The crude product was purified by chromatography on a silica gelcolumn eluted with a gradient from hexanes to 20% EtOAc:hexanes to give0.32 g (65%) of the title compound as a yellow viscous oil. ¹H NMR (400MHz, CDCl₃): δ 1.21 (s, 6H), 1.23 (s, 6H), 1.33 (t, J=7.1 Hz, 3H), 2.22(s, 2H), 2.23 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 5.47 (s, 1H), 6.41 (d,J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.11 (d, J=1.6 Hz, 1H), 7.17 (d,J=8.3 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.66 (d, J=15.9 Hz, 1H). LCMS(ESI), m/z, 455 (M+H)⁺, 453 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-Chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoicacid (132)

To a solution ofEthyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (131) (0.32 g,0.70 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added anaqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C.for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueoussolution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). Thecombined organic extract washed with brine and dried over Na₂SO₄. Uponconcentration and adding hexanes, the title compound 132 was obtained asa white powder (0.255 g, 85%). mp 118-121° C. ¹H NMR (400 MHz, DMSO-d₆):δ 1.10 (s, 6H), 1.12 (s, 6H), 2.11 (s, 2H), 2.13 (s, 2H), 6.47 (d,J=15.9 Hz, 1H), 6.85-7.00 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 7.19 (d,J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 10.15(s, 1H), 12.36 (s, 1H). LCMS (ESI): m/z 425 (M−H)⁻. Anal. Calcd forC₂₅H₂₇ClO₄.0.2H₂O: C, 69.74; H, 6.41; Found: C, 69.82; H, 6.56.

Example 45 (135)

Step 1: 4-[(4-Bromophenyl)(cycloheptylidene)methyl]-2-fluorophenol (133)

To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20mL) was slowly added TiCl₄ (0.45 mL, 4.07 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02mmol) and cycloheptanone (0.35 g, 3.05 mmol) in THF (6 mL) was added tothe mixture. The reaction mixture was heated at reflux with stirringunder a nitrogen atmosphere for 1.5 h. The reaction mixture was allowedto cool to room temperature. To the reaction mixture was slowly added10% aqueous K₂CO₃ (20 mL). The reaction mixture was filtered through apad of Celite and the pad washed with EtOAc (100 mL). The filtrate wastransferred to a separatory funnel and the layers were separated. Theaqueous layer was further extracted with EtOAc (25 mL). The combinedorganic phase washed with brine, dried over Na₂SO₄, filtered, and thefiltrate was concentrated to give the crude product as brown oil. Thecrude product was purified by flash chromatography on silica gel withhexanes:EtOAc (100:0 to 20:1) to give 0.30 g (79%) of compound 133 as ayellow solid. mp 102-104° C. ¹H NMR (400 MHz, CDCl₃): δ 1.56 (br s, 8H), 2.20-2.35 (m, 4 H), 4.96 (br s, 1H), 6.75-6.86 (m, 2H), 6.90 (t,J=8.6 Hz, 1H), 7.00 (d, J=8.3 Hz, 2 H), 7.39 (d, J=8.3 Hz, 2H). LCMS(ES): m/z 373 (M−H)⁻.

Step 2:Ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate(134)

To a round-bottomed flask were added4-[(4-bromophenyl)(cycloheptylidene)methyl]-2-fluorophenol (133) (0.30g, 0.80 mmol), ethyl acrylate (0.88 mL, 8.00 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol),triethylamine (0.56 mL, 4.00 mmol) and DMF (10 mL). The stirred reactionmixture was heated overnight at 100° C. under a nitrogen atmosphere. Thereaction mixture was allowed to cool to room temperature and transferredto a separatory funnel with the aid of water and EtOAc (100 mL). Thelayers were separated and the organic phase washed with water, brine,dried over Na₂SO₄, filtered, and the filtrate was concentrated to givereddish brown oil. The crude product was purified by chromatography on asilica gel column eluted with a gradient from hexanes to 15%EtOAc:hexanes to give 0.22 g (70%) of compound 134 as a colorlessviscous oil. ¹H NMR (400 MHz, CDCl₃): δ 1.33 (t, J=7.1 Hz, 3H), 1.57 (brs, 8H), 2.25-2.35 (m, 4H), 4.25 (q, J=7.1 Hz, 2H), 4.99 (d, J=4.0 Hz,1H), 6.39 (d, J=15.9 Hz, 1H), 6.75-6.88 (m, 2H), 6.91 (t, J=8.7 Hz, 1H),7.14 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65 (d, J=16.0 Hz, 1H).LCMS (ES): m/z, 395 (M+H)⁺, 393 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoicacid (135)

To a solution ofethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate(134) (0.22 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) wasadded an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with anaqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50mL). The combined organic extract washed with brine and dried overNa₂SO₄. Upon concentration, light brown foam was obtained. It wastriturated with hexanes (contains 1% MeOH) to give compound 135 as apale yellow solid (0.171 g, 84%). mp 164-165° C. ¹H NMR (400 MHz,DMSO-d₆): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H),6.70-6.78 (m, 1H), 6.80-6.90 (m, 1H), 7.14 (d, J=8.2 Hz, 2H), 7.53 (d,J=16.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 9.74 (s, 1H), 12.35 (s, 1H).LCMS (ES): m/z 367 (M+H)⁺, m/z 365 (M−H)⁻. Anal. Calcd for C₂₃H₂₃FO₃.0.1H₂O: C, 75.02; H, 6.35; Found: C, 74.93; H, 6.44.

Example 46 (138)

Step 1:4-[(4-Bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-fluorophenol(136)

To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20mL) was slowly added TiCl₄ (0.45 mL, 4.07 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.49 g, 3.05mmol) in THF (6 mL) was added to the mixture. The reaction mixture washeated at reflux with stirring under a nitrogen atmosphere for 1.5 h.The reaction mixture was allowed to cool to room temperature. To thereaction mixture was slowly added 10% aqueous K₂CO₃ (20 mL). Thereaction mixture was filtered through a pad of Celite and the pad waswashed with EtOAc (100 mL). The filtrate was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was furtherextracted with EtOAc (25 mL). The combined organic phase washed withbrine, dried over Na₂SO₄, filtered, and the filtrate was concentrated togive the crude product as yellow oil. The crude product was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 15% EtOAc:hexanes to give 0.40 g (94%) of compound 136 as ayellow foam. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 6H), 1.22 (s, 6H), 2.18(s, 2H), 2.23 (s, 2H), 5.04 (d, J=4.0 Hz, 1H), 6.80-6.88 (m, 2H), 6.93(t, J=8.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H). LCMS(ES): m/z 417 (M−H)⁻.

Step 2:Ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate(137)

To a round-bottomed flask were added4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-fluorophenol(136) (0.40 g, 0.95 mmol), ethyl acrylate (1.05 mL, 9.54 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.067 g, 0.10 mmol), Et₃N(0.70 mL, 4.77 mmol) and DMF (12 mL). The stirred reaction mixture washeated overnight at 100° C. under a nitrogen atmosphere. The reactionmixture was allowed to cool to room temperature and transferred to aseparatory funnel with the aid of water and EtOAc (100 mL). The layerswere separated and the organic phase washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated to give brownoil. The crude product was purified by chromatography on a silica gelcolumn eluted with a gradient from hexanes to 20% EtOAc:hexanes to give0.31 g (74%) of the title compound 137 as a light yellow foam. ¹H NMR(400 MHz, CDCl3): δ 1.21 (s, 6H), 1.23 (s, 6H), 1.33 (t, J=7.1 Hz, 3H),2.22 (s, 2H), 2.24 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 5.44 (br s, 1H),6.40 (d, J=15.9 Hz, 1H), 6.80-6.90 (m, 2H), 6.93 (t, J=8.5 Hz, 1H), 7.17(d, J=8.1 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H). LCMS(ES): m/z, 439 (M+H)⁺, 437 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoicacid (138)

To a solution ofethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (137) (0.30 g,0.68 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added anaqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C.for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueoussolution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). Thecombined organic extract washed with brine and dried over Na₂SO₄. Uponconcentration and adding hexanes, the title compound 138 was obtained asan off-white solid (0.227 g, 81%). mp 125-128° C. ¹H NMR (400 MHz,DMSO-d₆): δ1.10 (s, 6H), 1.12 (s, 6H), 2.10 (s, 2H), 2.14 (s, 2H), 6.47(d, J=15.9 Hz, 1H), 6.75-6.80 (m, 1H), 6.82-6.95 (m, 2H), 7.19 (d, J=8.2Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 9.80 (s, 1H),12.36 (s, 1H). LCMS (ES): m/z 409 (M−H)⁻. Anal. Calcd forC₂₅H₂₇FO₄.0.4H₂O: C, 71.89; H, 6.71; Found: C, 71.88; H, 6.92.

Example 47 (141)

Step 1:4-[(4-Bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-fluorophenol(139)

To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20mL) was slowly added TiCl₄ (0.45 mL, 4.07 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of(4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.48 g, 3.05 mmol) in THF(6 mL) was added to the mixture. The reaction mixture was heated atreflux with stirring under a nitrogen atmosphere for 1 h. The reactionmixture was allowed to cool to room temperature. To the reaction mixturewas slowly added 10% aqueous K₂CO₃ (20 mL). The reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc (100 mL).The filtrate was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was further extracted with EtOAc (25 mL).The combined organic phase washed with brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asyellow oil. The crude product was purified by flash chromatography onsilica gel with hexanes:EtOAc (100:0 to 30:1) to give 0.33 g (78%) ofcompound 139 as a light yellow viscous oil. ¹H NMR (400 MHz, CDCl₃): δ0.91 (s, 6H), 0.93 (s, 6H), 1.29 (s, 2H), 1.92 (s, 2H), 1.97 (s, 2H),4.99 (d, J=3.8 Hz, 1H), 6.78-6.87 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.01(d, J=8.3 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H). LCMS (ES): m/z 415 (M−H)⁻.

Step 2: Ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (140)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-fluorophenol (139) (0.33 g, 0.79 mmol), ethylacrylate (0.87 mL, 7.90 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol), Et₃N(0.55 mL, 3.95 mmol) and DMF (10 mL). The stirred reaction mixture washeated overnight at 100° C. under a nitrogen atmosphere. The reactionmixture was allowed to cool to room temperature and transferred to aseparatory funnel with the aid of water and EtOAc (100 mL). The layerswere separated and the organic phase washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated to give brownoil. The crude product was purified by chromatography on a silica gelcolumn eluted with a gradient from hexanes to 15% EtOAc:hexanes to give0.235 g (68%) of compound 140 as a light yellow viscous oil. ¹H NMR (400MHz, CDCl3): δ 0.92 (s, 6H), 0.94 (s, 6H), 1.29 (s, 2H), 1.32 (t, J=7.1Hz, 3H), 1.95 (s, 2H), 1.97 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.98 (d,J=4.2 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 6.80-6.95 (m, 3H), 7.16 (d,J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.65 (d, J=16.1 Hz, 1H). LCMS(ES): m/z, 437 (M+H)⁺, 435 (M−H)⁻.

Step 3:(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoicacid (141)

To a solution ofEthyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (140) (0.235 g, 0.54 mmol)in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solutionof 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Uponcooling, the mixture was acidified to pH=2 with an aqueous solution of 2N HCl. The mixture was extracted with EtOAc (2×50 mL). The combinedorganic extract washed with brine and dried over Na₂SO₄. Uponconcentration and adding hexanes, compound 141 was obtained as paleyellow solid (0.182 g, 83%). mp 193-195° C. ¹H NMR (400 MHz, DMSO-d₆): δ0.87 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.88 (s, 2H), 1.91 (s, 2H),6.45 (d, J=15.9 Hz, 1H), 6.76 (dd, J₁=8.2 Hz, J₂=1.6 Hz, 1H), 6.80-6.92(m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.2Hz, 2H), 9.72 (s, 1H), 12.32 (s, 1H). LCMS (ES): m/z 407 (M−H)⁻. Anal.Calcd for C₂₆H₂₉FO₃.⅙H₂O: C, 75.89; H, 7.19; Found: C, 75.91; H, 7.17.

Example 48 (145)

Step 1: (4-Iodophenyl)[4-(methyloxy)phenyl]methanone (142)

4-Iodobenzoic acid (3.0 g, 11.58 mmol) was suspended in CH₂Cl₂ (50 mL).Oxalyl chloride (2.20 mL, 23.71 mmol) was added dropwise, followed byaddition of three drops of DMF. The reaction mixture was stirred at roomtemperature for 3 h. CH₂Cl₂ and the excess of oxalyl chloride wereremoved under vacuum. The residue was dissolved in CH₂Cl₂ (35 mL) withanisole (1.70 mL, 15.41 mmol). Cooled in an ice bath, AlCl₃ (2.40 g,17.78 mmol) was added in portions. The mixture was stirred at 0° C. for3 h, poured into 1 N HCl (50 mL) with ice, the mixture was extractedwith CH₂Cl₂ (2×100 mL). The combined CH₂Cl₂ extract washed withsaturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered, and thefiltrate was concentrated to give brown solid. The crude product wastriturated with hot hexanes to give 3.91 g (98%) of compound 142 aslight beige solid. ¹H NMR (400 MHz, CDCl₃): δ 3.89 (s, 3H), 6.96 (d,J=8.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.83 (d,J=8.5 Hz, 2H). LCMS (APCI): m/z, 339 (M+H)⁺.

Step 2: (4-Hydroxyphenyl)(4-iodophenyl)methanone (143)

A mixture of (4-Iodophenyl)[4-(methyloxy)phenyl]methanone (142) (1.50 g,4.44 mmol) and AlCl₃ (2.40 g, 17.74 mmol) were refluxed in benzene (50mL) for 1.5 h and then cooled to 0° C. in an ice bath. Water (50 mL) wasadded slowly, and the mixture was extracted with ether (2×100 mL). Thecombined ethereal extracts were washed with water, brine, and dried overNa₂SO₄. Concentration and trituration with hot hexanes afforded 1.36 g(95%) of the title compound as light brown solid. ¹H NMR (400 MHz,CDCl₃): δ 5.37 (br s, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.4 Hz,2H), 7.75 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). LCMS (ESI): m/z,325 (M+H)⁺, 323 (M−H)⁻.

Step 3:4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)

To a stirred suspension of zinc powder (2.20 g, 33.6 mmol) in THF (75mL) was slowly added TiCl₄ (1.85 mL, 16.8 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of (4-hydroxyphenyl) (4-iodophenyl)methanone(143) (1.36 g, 4.20 mmol) and 3,3,5,5-tetramethylcyclohexanone (1.98 g,12.6 mmol) in THF (20 mL) was added to the mixture. The reaction mixturewas heated at reflux with stirring under a nitrogen atmosphere for 25minutes. The reaction mixture was allowed to cool to room temperature.To the reaction mixture was slowly added 10% aqueous K₂CO₃ (75 mL). Thereaction mixture was filtered through a pad of Celite and the pad waswashed with EtOAc (200 mL). The filtrate was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was furtherextracted with EtOAc (50 mL). The combined organic phase washed withwater, brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated to give the crude product as yellow oil. The crude productwas purified by chromatography on a silica gel column eluted with agradient from hexanes to 15% EtOAc:hexanes to give a solid residue,which was triturated with hot hexanes to afford 1.03 g (55%) compound144 as white solid. mp 148-149° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (s,6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.85 (s, 2H), 1.89 (s, 2H), 6.65 (d,J=8.4 Hz, 2H), 6.85-6.95 (m, 4H), 7.61 (d, J=8.3 Hz, 2H), 9.29 (s, 1H).LCMS (ESI): m/z 445 (M−H)⁻.

Step 4:4-[[4-(3-hydroxy-1-propyn-1-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(145)

To a degassed solution of4-[(4-iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)(0.17 g, 0.38 mmol) in DMF (3 mL) were added Pd(PPh₃)₂Cl₂ (27 mg, 0.04mmol), CuI (8 mg, 0.04 mmol), N,N-diisopropylethylamine (0.30 mL, 1.71mmol) and propargyl alcohol (45 μL, 0.76 mmol). The reaction mixture wasstirred at room temperature overnight, poured into saturated aqueousNH₄Cl (15 mL) and water (5 mL), extracted with EtOAc (3×50 mL). Thecombined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asbrown oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 30% EtOAc:hexanes togive 0.106 g (74%) of compound 145 as pale yellow solid. mp 141-142° C.¹H NMR (400 MHz, DMSO-d₆): δ 0.85 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H),1.85 (s, 2H), 1.89 (s, 2H), 4.25 (d, J=5.9 Hz, 2H), 5.28 (t, J=5.9 Hz,1H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.0 Hz,2H), 7.31 (d, J=8.0 Hz, 2H), 9.29 (s, 1H). LCMS (ESI): m/z 375 (M+H)⁺,373 (M−H)⁻. Anal. Calcd for C₂₆H₃₀O₂.0.1H₂O: C, 82.98; H, 8.09; Found:C, 82.88; H, 8.19.

Example 49 (147)

Step 1:4-((3,3,5,5-Tetramethylcyclohexylidene){4-[(trimethylsilyl)ethynyl]phenyl}methyl)phenol(146)

To a degassed solution of4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)(0.305 g, 0.68 mmol) in DMF (8 mL) were added Pd(PPh₃)₂Cl₂ (48 mg, 0.07mmol), CuI (13 mg, 0.07 mmol), N,N-diisopropylethylamine (0.55 mL, 3.10mmol) and trimethylsilyl acetylene (0.12 mL, 0.82 mmol). The reactionmixture was stirred at room temperature overnight, poured into saturatedaqueous NH₄Cl (20 mL) and water (10 mL), extracted with EtOAc (2×50 mL).The combined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asdark brown oil. The crude product was purified by chromatography on asilica gel column eluted with a gradient from hexanes to 15%EtOAc:hexanes to give light brown solid, which washed with cold hexanesto yield 0.18 g (64%) of the title compound 146 as an off-white solid.¹H NMR (400 MHz, CDCl₃): δ 0.22 (s, 9H), 0.89 (s, 6H), 0.92 (s, 6H),1.27 (s, 2H), 1.91 (s, 2H), 1.97 (s, 2H), 4.55 (br s, 1H), 6.72 (d,J=8.5 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 7.36 (d,J=8.3 Hz, 2H). LCMS (ESI): m/z 415 (M−H)⁻.

Step 2:4-[(4-Ethynylphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(147)

4-((3,3,5,5-Tetramethylcyclohexylidene){4-[(trimethylsilyl)ethynyl]phenyl}methyl)phenol(146) (0.175 g, 0.42 mmol) was dissolved in MeOH (10 mL). To thissolution was added K₂CO₃ (0.18 g, 1.26 mmol). The reaction mixture wasstirred at room temperature overnight, poured into water (10 mL) andextracted with EtOAc (2×50 mL). The combined organic phase washed withbrine, dried over Na₂SO₄, filtered, and the filtrate was concentrated togive the crude product as brown solid. The crude product was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 15% EtOAc:hexanes to give 0.14 g (97%) of the title compound147 as white solid. mp 138-139° C. ¹H NMR (400 MHz, CDCl₃): δ 0.91 (s,6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.93 (s, 2H), 1.97 (s, 2H), 3.03 (s,1H), 4.55 (br s, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H),7.11 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H). LCMS (ESI): m/z 343(M−H)⁻.

Example 50 (149)

Step 1: Ethyl3-{4-[(4-{([(ethyloxy)carbonyl]oxy}phenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoate (148)

Tris(dibenzylidene acetone) dipalladium (10 mg, 0.01 mmol) andP(o-tolyl)₃ (14 mg, 0.04 mmol) were stirred in CH₂Cl₂ (2 mL) at roomtemperature for 1 h. To this mixture was added1,2,2,6,6-pentamethylpiperidine (0.15 mL, 0.81 mmol) followed by asolution of4-[(4-ethynylphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(147) (0.127 g, 0.37 mmol) and catalytic amount of DMAP in CH₂Cl₂ (2mL). The resulting mixture was heated under slow reflux. Ethylchloroformate (0.12 mL, 1.18 mmol) was added dropwise. The reactionmixture was stirred at 40° C. overnight, poured into water, extractedwith EtOAc (2×30 mL). The combined organic phase washed with brine,dried over Na₂SO₄, filtered, and the filtrate was concentrated to givethe crude product as brown oil. The crude product was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 15% EtOAc:hexanes to yield 88 mg (49%) of compound 148 asyellow oil. ¹H NMR (400 MHz, CDCl₃): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29(s, 2H), 1.30-1.40 (m, 6H), 1.93 (s, 2H), 1.96 (s, 2H), 4.20-4.35 (m,4H), 7.05-7.20 (m, 6H), 7.49 (d, J=7.9 Hz, 2H). LCMS (ESI): m/z 489(M+H)⁺.

Step 2:3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoicacid (149)

To a solution of ethyl3-{4-[(4-{[(ethyloxy)carbonyl]oxy}phenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoate (148) (88 mg, 0.18 mmol) ina mixture of EtOH (4 mL) and THF (4 mL) was added an aqueous solution of1 N NaOH (5 mL). The mixture was stirred at 60° C. for 2 h. Uponcooling, the mixture was acidified to pH=2 with an aqueous solution of 1N HCl. The mixture was extracted with EtOAc (2×50 mL). The combinedorganic extract washed with water, brine and dried over Na₂SO₄. Uponconcentration and trituration with hot 1:1 hexanes/ether (contained 1%of methanol), (35 mg (50%) of compound 149 was obtained as white solid.mp 172-174° C. (dec.). ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (s, 6H), 0.87(s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.91 (s, 2H), 6.66 (d, J=8.4 Hz,2H), 6.92 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz,2H), 9.31 (s, 1H), 13.73 (s, 1H). HRMS (EI) Calcd for C₃₂H₄₄O₃Si₂:532.2829 (M⁺); Found: 532.1591.

Example 51 (154)

Step 1: 4-[2-(Methyloxy)-2-oxoethyl]benzoic acid (150)

To a suspension of 4-(carboxymethyl)benzoic acid (2.43 g, 13.5 mmol) inmethanol (30 mL) was added thionyl chloride (50 μL, 0.67 mmol). Thereaction mixture was stirred at room temperature for 5.5 h, and a clearsolution was obtained. The solvent was removed under reduced pressure.The residue was taken up in ether (100 mL), washed with saturatedaqueous NaHCO₃ (2×50 mL) and water (30 mL). The combined NaHCO₃ andwater extract was acidified with concentrated HCl in an ice bath. Thewhite precipitation was collected and washed with water, dried to yield2.30 g (88%) compound 150 as white solid. The material was used withoutfurther purification. mp 134-136° C. ¹H NMR (400 MHz, CDCl₃): δ 3.71 (s,5H), 7.40 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H). LCMS (ESI), m/z,193 (M−H)⁻.

Step 2: Methyl(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetate (151)

4-[2-(Methyloxy)-2-oxoethyl]benzoic acid (150) (1.0 g, 5.15 mmol) wasdissolved in CH₂Cl₂(25 mL). Oxalyl chloride (0.92 mL, 10.3 mmol) wasadded dropwise, followed by addition of two drops of DMF. The reactionmixture was stirred at room temperature for 2 h. CH₂Cl₂ and the excessof oxalyl chloride were removed under vacuum. The residue was dissolvedin CH₂Cl₂ (15 mL) with anisole (0.74 mL, 6.70 mmol). Cooled in an icebath, AlCl₃ (1.04 g, 7.73 mmol) was added in portions. The mixture wasstirred at 0° C. for 4 h, then stirred at room temperature for 20minutes. Poured into 1 N HCl (25 mL) with ice, the mixture was extractedwith CH₂Cl₂ (2×60 mL). The combined CH₂Cl₂ extract washed with saturatedaqueous NaHCO₃, brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated to give yellow oil. The crude product was purified bychromatography on a silica gel column eluted with hexanes:EtOAc (5:1) togive 1.00 g (68%) of compound 151 as colorless oil. ¹H NMR (400 MHz,CDCl₃): δ 3.71 (s, 2H), 3.72 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz,2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.8 Hz,2H). LCMS (ESI): m/z, 285 (M+H)⁺, 283 (M−H)⁻.

Step 3: Methyl{4-[(4-hydroxyphenyl)carbonyl]phenyl}acetate (152)

A mixture of methyl(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetate(151) (1.00 g, 3.52 mmol) and AlCl₃ (1.90 g, 14.07 mmol) were refluxedin benzene (40 mL) for 1 h and then cooled to 0° C. in an ice bath.Water (35 mL) was added slowly, and the mixture was extracted with ether(2×50 mL, each contained 15 mL of EtOAc). The combined ethereal extractwashed with water, brine, and dried over Na₂SO₄. Concentration gavelight brown oil, which was purified by chromatography on a silica gelcolumn eluted with a gradient from hexanes to 45% EtOAc:hexanes toafford 0.86 g (90%) of compound 152 as colorless oil. ¹H NMR (400 MHz,CDCl₃): δ 3.71 (s, 2H), 3.72 (s, 3H), 5.63 (br s, 1H), 6.89 (d, J=8.6Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.6Hz, 2H), 8.24 (d, J=7.9 Hz, 1H). LCMS (ESI): m/z 271 (M+H)⁺, 269 (M−H)⁻.

Step 4:Methyl{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate(153)

To a stirred suspension of zinc powder (1.67 g, 25.45 mmol) in THF (60mL) was slowly added TiCl₄ (1.40 mL, 12.72 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of methyl{4-[(4-hydroxyphenyl)carbonyl]phenyl}acetate (152) (0.86 g, 3.18 mmol)and 3,3,5,5-tetramethyl cyclohexanone (1.50 g, 9.55 mmol) in THF (20 mL)was added to the mixture. The reaction mixture was heated at reflux withstirring under a nitrogen atmosphere for 1.5 h. The reaction mixture wasallowed to cool to room temperature. To the reaction mixture was slowlyadded 10% aqueous K₂CO₃ (60 mL). The reaction mixture was filteredthrough a pad of Celite and the pad washed with EtOAc (150 mL). Thefiltrate was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was further extracted with EtOAc (50 mL).The combined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asbrown oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 20% EtOAc:hexanes togive light brown oil, which upon adding hexanes solidified. The solidwas triturated with hot hexanes to afford 0.90 g (72%) of 153 as a whitesolid. mp 154-155° C. ¹H NMR (400 MHz, CDCl₃): δ 0.91 (s, 6H), 0.92 (s,6H), 1.27 (s, 2H), 1.95 (s, 2H), 1.96 (s, 2H), 3.58 (s, 2H), 3.68 (s,3H), 4.56 (br s, 1H), 6.72 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H),7.10 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 393(M+H)⁺, 391 (M−H)⁻.

Step 5:{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}aceticacid (154)

To a solution ofmethyl{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate(153) (0.20 g, 0.51 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) wasadded an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with anaqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50mL). The combined organic extract washed with brine and dried overNa₂SO₄. Upon concentration and trituration with hot hexanes (containing1% methanol), the title compound 154 was obtained as a white solid(0.185 g, 96%). mp 220-221° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (s,6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 3.49 (s,2H), 6.64 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.1 Hz,2H), 7.14 (d, J=8.1 Hz, 2H), 9.24 (s, 1H), 12.26 (s, 1H). LCMS (ESI):m/z 401 (M+Na)⁺, 377 (M−H)⁻. Anal. Calcd for C₂₅H₃₀O₃. ⅙H₂O: C, 78.71;H, 8.01; Found: C, 78.73; H, 7.98.

Example 52 (155)

Step 1: 4-[Cycloheptylidene(4-hydroxyphenyl)methyl]benzoic acid (155)

To a 3-necked round-bottomed flask equipped with a reflux condenser,magnetic stir bar, and two nitrogen inlets, were added zinc powder (0.39g, 5.97 mmoL), and anhydrous THF (15 mL). To the stirred suspension wasadded TiCl₄ (0.31 mL, 0.54 g, 2.83 mmoL) slowly via syringe at RT undera nitrogen atmosphere. (Note: significant fuming occurred during TiCl₄addition. Two nitrogen inlets were used to accommodate the possibletransient pressure increase during TiCl₄ addition). The reaction mixturewas heated at reflux with stirring under a nitrogen atmosphere for 2.5h. A solution of cycloheptanone (0.26 mL, 0.25 g, 2.23 mmoL) and methyl4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.19 g, 0.74 mmoL) in THF(15 mL) was added to the reaction mixture. The stirred reaction mixturewas heated at reflux under a nitrogen atmosphere for 2 h. The oil bathwas removed and the reaction mixture was allowed to cool at RT. To thestirred reaction mixture was added H₂O (5 mL) followed by 10% aqueousK₂CO₃ (5 mL). The quenched reaction mixture was filtered through a padof Celite with the aid of H₂O and EtOAc. The filtrate was transferred toa separatory funnel and the layers were separated. The organic phase wasdried (MgSO₄), filtered, and the filtrate was concentrated to give thecrude product as a yellow liquid. The crude product was partiallypurified by flash chromatography on silica gel using a CH₂Cl₂:MeOHgradient (100:0 to 95:5) to give 0.228 g of the impure methyl ester as acolorless oil. To a solution of methyl4-[cycloheptylidene(4-hydroxyphenyl)methyl]benzoate (0.23 g) in THF (3mL) and EtOH (3 mL) was added 1 N NaOH (6 mL) at RT under a nitrogenatmosphere. The stirred reaction mixture was heated at 85° C. under anitrogen atmosphere for 4 h. The oil bath was removed and the reactionmixture was allowed to stand at RT overnight. The reaction mixture waspartially concentrated in vacuo to remove the THF and EtOH. To the basicaqueous solution was added 1 N HCl to pH ˜1 (as judged by litmus paper).The turbid acidic aqueous mixture was transferred to a separatory funnelwith the aid of H₂O and CH₂Cl₂ and the layers were separated. Theorganic phase was dried (MgSO₄), filtered, and the filtrate wasconcentrated to give the crude product as a white solid. The crudeproduct was purified by reverse phase preparative HPLC using a C-18column and a CH₃CN:H₂O gradient (50:50 to 100:0) with 0.05% TFA as amodifier to give 0.070 g (29% over two steps) of the title compound 155as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.51 (m, 8 H), 2.17 (m, 2H), 2.24 (m, 2 H), 6.66 (d, J=8.6 Hz, 2 H), 6.91 (d, J=8.4 Hz, 2 H),7.21 (d, J=8.1 Hz, 2 H), 7.84 (d, J=8.0 Hz, 2 H), 9.31 (s, 1 H), 12.81(s, 1 H). HRMS (ESI) Calcd for C₂₁H₂₁O₃: 321.1491 (M−H)⁻. Found:321.1513.

Example 53 (157)

Step 1: Methyl 4-[cyclohexylidene(4-hydroxyphenyl)methyl]benzoate (156)

To a 3-necked round-bottomed flask were added zinc powder (0.40 g, 6.12mmoL) and anhydrous THF (15 mL). To the stirred suspension was slowlyadded by syringe TiCl₄ (0.32 mL, 0.55 g, 2.9 mmoL) at RT under anitrogen atmosphere. The reaction mixture was heated at reflux for 2 h.A solution of cyclohexanone (0.24 mL, 0.227 g, 2.3 mmoL) and methyl4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.20 g, 0.78 mmoL) inanhydrous THF (5 mL) was added to the reaction mixture. The reactionmixture was heated a reflux for 2 h. The oil bath was removed and thereaction mixture was allowed to cool at RT. To the reaction mixture wasadded H₂O (5 mL) followed by 10% K₂CO₃ (5 mL). The quenched reactionmixture was filtered through a pad of Celite with the aid of H₂O andEtOAc. The filtrate was transferred to a separatory funnel and thelayers were separated. The organic phase was dried (MgSO₄), filtered,and the filtrate was concentrated to give the crude product as a yellowoil. The crude product was purified by flash chromatography on silicagel with a CH₂Cl₂:MeOH gradient (100:0 to 95:5) to give 0.176 g (70%) ofcompound 156 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (m, 6H), 2.10 (m, 2 H), 2.17 (m, 2 H), 3.80 (s, 3 H), 6.66 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.2 Hz, 2 H), 7.17 (d, J=8.1 Hz, 2 H), 7.86 (d, J=7.8 Hz,2 H), 9.34 (s, 1 H).

Step 2: 4-[Cyclohexylidene(4-hydroxyphenyl)methyl]benzoic acid (157)

To a solution of methyl4-[cyclohexylidene(4-hydroxyphenyl)methyl]benzoate (156) (0.175 g, 0.54mmoL) in THF (3 mL) and EtOH (3 mL) was added 1 N NaOH (6 mL) at RT. Thereaction mixture was heated between 85-90° C. under a nitrogenatmosphere for 2 h. The oil bath was removed and the reaction mixturewas allowed to cool to RT. The reaction mixture was partiallyconcentrated in vacuo to remove the THF and EtOH. The basic aqueousmixture was diluted with H₂O and the pH was adjusted to ˜1 (as judged bylitmus paper) with 1 N HCl. The acidic aqueous mixture was extractedwith CH₂Cl₂ (2×). The organic extracts were combined, dried (MgSO₄),filtered, and the filtrate was concentrated to give the 0.087 g (52%) ofcompound 157 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (m, 6H), 2.11 (m, 2 H), 2.17 (m, 2 H), 6.67 (d, J=8.5 Hz, 2 H), 6.85 (d,J=8.5 Hz, 2 H), 7.15 (d, J=8.1 Hz, 2 H), 7.84 (d, J=8.3 Hz, 2 H), 9.35(s, 1 H), 12.81 (br s, 1). LRMS (ESI): m/z 307 (M−H)⁻.

Example 54 (159)

Step 1: Methyl 4-[cyclooctylidene(4-hydroxyphenyl)methyl]benzoate (158)

To a 3-neck round-bottomed flask was added zinc powder (0.40 g, 6.12mmoL) followed by anhydrous THF (15 mL). To the stirred suspension wasslowly added TiCl₄ (0.32 mL, 0.55 g, 2.9 mmoL) at RT under a nitrogenatmosphere. The reaction mixture was heated at reflux for 2 h. To thereaction mixture was added a solution of methyl4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.193 g, 0.75 mmoL) andcyclooctanone (0.31 g, 2.46 mmoL) in anhydrous THF (5 mL). The reactionmixture was heated at reflux under a nitrogen atmosphere to 2 h. The oilbath was removed and the reaction mixture was allowed to cool at RT. Tothe reaction mixture was added H₂O (5 mL) followed by 10% K₂CO₃ (5 mL).The reaction mixture was filtered through a pad of Celite with the aidof H₂O and EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The organic phase was dried (MgSO₄),filtered, and the filtrate was concentrated to give a yellow oil. Thecrude product was purified by flash chromatography on silica gel with aCH₂Cl₂:MeOH gradient (100:0 to 95:5) to give 0.159 g (60%) of compound158 as an oil. ¹H NMR (400 MHz, DMSO-d₆): δ 1.36-1.54 (m, 8 H), 1.59 (m,2 H), 2.14 (m, 2 H), 2.20 (m, 2 H), 3.80 (s, 3 H), 6.67 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.3 Hz, 2 H), 7.26 (d, J=8.1 Hz, 2 H), 7.87 (d, J=8.1 Hz,2 H), 9.30 (s, 1 H).

Step 2: 4-[Cyclooctylidene(4-hydroxyphenyl)methyl]benzoic acid (159)

To methyl 4-[cyclooctylidene(4-hydroxyphenyl)methyl]benzoate (158)(0.159 g, 0.45 mmoL) was added THF (3 mL) and EtOH (3 mL) followed by 1N NaOH (6 mL). The stirred reaction mixture was heated between 85-90° C.under a nitrogen atmosphere for 2 h. The oil bath was removed and thereaction mixture was allowed to cool at RT. The reaction mixture waspartially concentrated in vacuo to remove the THF and EtOH. To the basicaqueous mixture was added water. The pH of the basic solution wasadjusted to ˜1 (according to litmus paper) with 1 N HCl. The acidicaqueous mixture was extracted with CH₂Cl₂ (2×). The organic extractswere combined, dried (MgSO₄), filtered, and the filtrate wasconcentrated in vacuo to give the crude product. The crude product waspurified by reverse phase preparative HPLC using a C-18 column with aCH₃CN:H₂O gradient (50:50 to 100:0) with 0.05% TFA as a modifier to give0.075 g (49%) of compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ1.38-1.56 (m, 8 H), 1.60 (m, 2 H), 2.15 (m, 2 H), 2.21 (m, 2 H), 6.68(d, J=8.4 Hz, 2 H), 6.94 (d, J=8.5 Hz, 2 H), 7.23 (d, J=8.1 Hz, 2 H),7.85 (d, J=8.1 Hz, 2 H), 9.30 (s, 1 H), 12.81 (s, 1 H). Anal. Calcd forC₂₂H₂₄O₃: C, 78.54; H, 7.19. Found: C, 78.29; H, 7.17

Example 55 (160)

Step 1:4-[[4-(1,3-Oxazol-2-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(160)

To a stirred suspension of4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoicacid (26) (0.373 g, 1.02 mmoL) in CH₂Cl₂ (10 mL) was added dropwise viasyringe oxalyl chloride (0.15 mL, 0.218 g, 1.72 mmoL) followed by DMF (4drops) at RT under a nitrogen atmosphere. Bubbling occurred uponaddition of DMF. After several minutes, CH₂Cl₂ (10 mL) was added and thereaction mixture was stirred at RT under a nitrogen atmosphere for 0.5h. The reaction mixture was concentrated in vacuo and toluene was addedto the residue. The toluene was removed in vacuo to give the crude acidchloride. To the crude acid chloride was added tetramethylene sulfone (3mL), K₂CO₃ (0.38 g, 2.75 mmoL) and 1H-1,2,3-triazole (0.065 mL, 0.077 g,1.12 mmoL). The stirred reaction mixture was heated overnight at 140° C.under a nitrogen atmosphere. The oil bath was removed and the reactionmixture was allowed to cool at RT. The crude reaction mixture wasapplied to an SiO₂ precolumn and the title compound was partiallypurified by flash chromatography on silica gel with a hexanes:EtOAcgradient (100:0 to 50:50) to give 0.072 g of the impure product as aviscous yellow oil. The impure product was purified by reverse phasepreparative HPLC using a C-18 column and a CH₃CN:H₂O gradient (75:25 to100:0) with 0.05% TFA as a modifier to give 0.023 g (6%) of compound 160as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.87 (s, 6 H), 0.89(s, 6 H), 1.26 (s, 2 H), 1.89 (s, 2 H), 1.93 (s, 2 H), 6.67 (d, J=8.5Hz, 2 H), 6.95 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.3 Hz, 2 H), 7.34 (s, 1H), 7.89 (d, J=8.3 Hz, 2 H), 8.18 (s, 1 H), 9.31 (s, 1 H). HRMS (ESI)Calcd for C₂₆H₃₀NO₂: 388.2277 (M+H)⁺. Found: 388.2288.

Example 56 (161)

Step 1:4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylcarboxamide(161)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.10 g, 0.21mmoL), benzamide 3-boronic acid (0.095 g, 0.58 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.022 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (5 mL). The stirredreaction mixture was heated at reflux under a nitrogen atmosphere for 3h. The oil bath was removed and the reaction mixture was allowed to coolat RT. The reaction mixture was partitioned between H₂O and CH₂Cl₂. Theorganic phase was separated, washed with H₂O followed by brine, driedover MgSO₄, filtered, and the filtrate was concentrated to give thecrude product as a dark brown oil. The crude product was partiallypurified by flash chromatography on silica gel with a CH₂Cl₂:MeOHgradient (100:0 to 98:2) to give 0.074 g of impure product. The impureproduct was purified by reverse phase preparative HPLC using a CH₃CN:H₂Ogradient (50:50 to 100:0) with 0.05% TFA as a modifier to give 0.024 g(26%) of compound 161 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H), 6.67 (d, J=8.4 Hz, 2 H),6.95 (d, J=8.4 Hz, 2 H), 7.22 (d, J=8.2 Hz, 2 H), 7.39 (br s, 1 H), 7.50(t, J=7.7 Hz, 1 H), 7.63 (d, J=8.1 Hz, 2 H), 7.80 (m, 2 H), 8.06 (br s,1 H), 8.12 (s, 1 H), 9.27 (s, 1 H). HRMS (ESI) Calcd for C₃₀H₃₄NO₂:440.2590 (M+H)⁺. Found: 440.2604.

Example 57 (162)

Step 1:4-[[4-(5-Pyrimidinyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(162)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.116 g, 0.25mmoL), pyrimidine-5-boronic acid (0.103 g, 0.83 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.022 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirredreaction mixture was heated at reflux under a nitrogen atmosphere for3.5 h. The oil bath was removed and the reaction mixture was allowed tocool at RT. The reaction mixture was transferred to a separatory funneland partitioned between H₂O and EtOAc. The organic phase was separatedand the aqueous phase was extracted with EtOAc. The organic extractswere combined, dried over MgSO₄, filtered, and the filtrate wasconcentrated in vacuo to give a brown oil. The crude product waspartially purified by flash chromatography on silica gel with ahexanes:EtOAc gradient (100:0 to 90:10) to give the impure product. Theimpure product was purified by reverse phase preparative HPLC with aC-18 column and a CH₃CN:H₂O gradient (75:25 to 100:0) with 0.05% TFA asa modifier to give 0.045 g (45%) of compound 162 as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H),6.67 (d, J=8.4 Hz, 2 H), 6.95 (d, J=8.4 Hz, 2 H), 7.26 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.3 Hz, 2 H), 9.11 (s, 2 H), 9.14 (s, 1 H), 9.29 (s, 1H). HRMS (ESI) Calcd for C₂₇H₃₁N₂O: 399.2436 (M+H)⁺. Found: 399.2437.

Example 58 (163)

Step 1:4-[[4′-(Methylsulfonyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(163)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.117 g, 0.25mmoL), 4-(methanesulphonyl)benzeneboronic acid (0.165 g, 0.82 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirredreaction mixture was heated at reflux under a nitrogen atmosphere for3.5 h. The oil bath was removed and the reaction mixture was allowed tocool at RT. The reaction mixture was transferred to a separatory funneland partitioned between H₂O and EtOAc. The organic phase was separatedand the aqueous phase was extracted with EtOAc. The organic extractswere combined, dried over MgSO₄, filtered, and the filtrate wasconcentrated in vacuo to give a brown oil. The crude product waspurified by flash chromatography on silica gel using a hexanes:EtOAcgradient (100:0 to 75:25) to give 0.063 g (53%) of compound 163 as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.26 (s, 2 H),1.93 (s, 4 H), 3.23 (s, 3 H), 6.67 (d, J=8.5 Hz, 2 H), 6.95 (d, J=8.4Hz, 2 H), 7.25 (d, J=8.2 Hz, 2 H), 7.67 (d, J=8.3 Hz, 2 H), 7.91 (d,J=8.6 Hz, 2 H), 7.95 (d, J=8.6 Hz, 2 H), 9.29 (s, 1 H). HRMS (ESI) Calcdfor C₃₀H₃₃O₃S: 473.2150 (M−H)⁻. Found: 473.2168.

Example 59 (164)

Step 1:(2E)-3-{4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-3-biphenylyl}-2-propenoicacid (164)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.117 g, 0.25mmoL), 3-(2-carboxyvinyl)benzeneboronic acid (0.117 g, 0.61 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.022 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirredreaction mixture was heated at reflux under a nitrogen atmosphere for 3h. The oil bath was removed and the reaction mixture was allowed to coolat RT.

The reaction mixture was transferred to a separatory funnel andpartitioned between H₂O and EtOAc. The organic phase was separated,dried (MgSO₄), filtered, and the filtrate was concentrated in vacuo togive an oil. The crude product was purified by reverse phase preparativeHPLC on a C-18 column with a CH₃CN:H₂O gradient (75:25 to 100:0) and0.05% TFA as a modifier to give 0.046 g (39%) of compound 164 as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.26 (s, 2H), 1.93 (s, 4 H), 6.63 (d, J=16.2 Hz, 1 H), 6.67 (d, J=8.4 Hz, 2 H),6.95 (d, J=8.5 Hz, 2 H), 7.20 (d, J=8.2 Hz, 2 H), 7.46 (t, J=7.7 Hz, 1H), 7.65 (m, 5 H), 7.95 (s, 1 H), 9.27 (s, 1 H), 12.39 (br s, 1 H).Anal. Calcd for C₃₂H₃₄O₃.0.25H₂O: C, 81.58; H, 7.38. Found: C, 81.62; H,7.33.

Example 60 (165)

Step 1:4-[[4-(3-Pyridinyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenoltrifluoroacetate (165)

To a round-bottomed flask were added4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.10 g, 0.21mmoL), pyridine-3-boronic acid (0.077 g, 0.63 mmoL),tetrakis(triphenylphosphine)palladium (0) (0.028 g, 0.024 mmoL), 2 MNa₂CO₃ (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirredreaction mixture was heated at reflux under a nitrogen atmosphere for 3h. The oil bath was removed and the reaction mixture was allowed to coolat RT. The reaction mixture was transferred to a separatory funnel andpartitioned between H₂O and EtOAc. The organic phase was separated,washed with brine, dried over MgSO₄, filtered, and the filtrate wasconcentrated in vacuo to give a brown-orange oil. The crude product waspurified by reverse phase preparative HPLC with a C-18 column and aCH₃CN:H₂O gradient (50:50 to 100:0) using 0.05% TFA as a modifier togive 0.018 g (17%) of compound 165 as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H), 6.67 (d,J=8.4 Hz, 2 H), 6.95 (d, J=8.4 Hz, 2 H), 7.25 (d, J=8.3 Hz, 2 H), 7.60(m, 1 H), 7.68 (d, J=8.0 Hz, 2 H), 8.24 (br d, J=8.0 Hz, 1 H), 8.60 (d,J=4.6 Hz, 1 H), 8.95 (m, 1 H), 9.29 (br s, 1 H). HRMS (ESI) Calcd forC₂₈H₃₂NO: 398.2484 (M+H)⁺. Found: 398.2484.

Example 61 (170)

Step 1: 4-[3-(Methyloxy)-3-oxopropyl]benzoic acid (166)

To a suspension of 3-(4-carboxyphenyl)propionic acid (2.0 g, 10.1 mmol)in methanol (20 mL) was added thionyl chloride (38 μL, 0.50 mmol). Thereaction mixture was stirred at room temperature for 16 h, and a clearsolution was obtained. The solvent was removed under reduced pressure.The residue was taken up in ether (100 mL), washed with saturatedaqueous NaHCO₃ (2×50 mL) and water (50 mL). The combined NaHCO₃ andwater extract was acidified with concentrated HCl in an ice bath. Theprecipitated white solid was collected, washed with water and dried toyield 1.76 g (84%) of compound 166 as off-white solid. The material wasused without further purification. mp 146-148° C. ¹H NMR (400 MHz,CDCl₃): δ 2.66 (t, J=7.7 Hz, 2H), 3.02 (t, J=7.7 Hz, 2H), 3.67 (s, 3H),7.30 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H). LCMS (ES), m/z, 209(M+H)⁺, 207 (M−H)⁻.

Step 2: Methyl 3-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)propanoate(167)

4-[3-(Methyloxy)-3-oxopropyl]benzoic acid (166) (1.0 g, 4.80 mmol) wasdissolved in CH₂Cl₂ (25 mL). Oxalyl chloride (0.86 mL, 9.61 mmol) wasadded dropwise, followed by addition of two drops of DMF. The reactionmixture was stirred at room temperature for 2 h. Methylene chloride andthe excess of oxalyl chloride were removed under vacuum. The residue wasdissolved in CH₂Cl₂ (15 mL) with anisole (1.05 mL, 9.60 mmol). Cooled inan ice bath, AlCl₃ (0.97 g, 7.20 mmol) was added in portions. Themixture was stirred at 0° C. for 3.5 h, then stirred at room temperaturefor 1.5 h. Poured into 1 N HCl (25 mL) with ice, the mixture wasextracted with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ extract washed withsaturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered, and thefiltrate was concentrated to give brown oil. The crude product waspurified by chromatography on a silica gel column eluted withhexanes:EtOAc (8:1 to 5:1) to give 0.90 g (63%) of the title compound167 as cotton-like white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.68 (t,J=7.7 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.89 (s, 3H), 6.96(d, J=8.8 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.81(d, J=8.8 Hz, 2H). LCMS (ESI): m/z 299 (M+H)⁺.

Step 3: Methyl 3-{4-[(4-hydroxyphenyl)carbonyl]phenyl}propanoate (168)

A mixture of methyl3-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)propanoate (167) (0.45 g,1.51 mmol) and AlCl₃ (0.82 g, 6.03 mmol) were refluxed in benzene (20mL) for 1 h and then cooled to 0° C. in an ice bath. Water (15 mL) wasadded slowly, and the mixture was extracted with ether (2×50 mL). Thecombined ethereal extract was washed with water, brine, and dried overNa₂SO₄. Concentration gave light brown oil, which was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 45% EtOAc:hexanes to afford 0.41 g (96%) of the titlecompound 168 as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 2.68 (t, J=7.7Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 3.68 (s, 3H), 5.44 (s, 1H), 6.89 (d,J=8.7 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.77 (d,J=8.8 Hz, 2H). LCMS (ESI): m/z 285 (M+H)⁺, m/z 283 (M−H)⁻.

Step 4: Methyl3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate(169)

To a stirred suspension of zinc powder (0.76 g, 11.54 mmol) in THF (30mL) was slowly added TiCl₄ (0.64 mL, 5.77 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The mixture was heated atreflux for 2 h. A solution of methyl3-{4-[(4-hydroxyphenyl)carbonyl]phenyl}propanoate (168) (0.41 g, 1.44mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.68 g, 4.33 mmol) in THF(10 mL) was added to the mixture. The reaction mixture was heated atreflux with stirring under a nitrogen atmosphere for 2 h. The reactionmixture was allowed to cool to room temperature. To the reaction mixturewas slowly added 10% aqueous K₂CO₃ (30 mL). The reaction mixture wasfiltered through a pad of Celite and the pad washed with EtOAc (100 mL).The filtrate was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was further extracted with EtOAc (25 mL).The combined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asyellow oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 20% EtOAc:hexanes togive light brown oil, which upon adding hexanes solidified. The solidwas triturated with hot hexanes to afford 0.40 g (68%) of compound 169as white solid. mp 129-130° C. ¹H NMR (400 MHz, CDCl₃): δ 0.92 (s, 12H),1.27 (s, 2H), 1.94 (s, 2H), 1.95 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.91(t, J=7.5 Hz, 2H), 3.66 (s, 3H), 4.57 (s, 1H), 6.73 (d, J=8.5 Hz, 2H),7.02 (d, J=8.4 Hz, 2H), 7.04-7.10 (m, 4H). LCMS (ESI): m/z 429 (M+Na)⁺,m/z 405 (M−H)⁻.

Step 5:3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoicacid (170)

To a solution of methyl3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate(9) (0.20 g, 0.49 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) wasadded an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with anaqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50mL). The combined organic extract washed with brine and dried overNa₂SO₄. Upon concentration and trituration with hot hexanes (contained1% methanol), the title compound 170 was obtained as white solid (0.177g, 92%). mp 243-244° C. ¹H NMR (400 MHz, CD₃OD): δ 0.91 (s, 6H), 0.92(s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.98 (s, 2H), 2.58 (t, J=7.7 Hz,2H), 2.87 (t, J=7.7 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.94 (d, J=8.5 Hz,2H), 7.05 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 393(M+H)⁺, m/z 391 (M−H)⁻.

Example 62 (172)

Step 1:4-[(4,4-Dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoicacid methyl ester (171)

To a slurry of zinc powder (0.26 g, 4.01 mmol) in dry tetrahydrofuran (9mL) was slowly added titanium tetrachloride (0.21 mL, 1.95 mmol). Thereaction mixture was heated at reflux for 2.5 h, then a solution of4,4-dimethyl-cyclohexanone (0.2 g, 1.58 mmol) and4-(4-hydroxy-benzoyl)-benzoic acid methyl ester (24) (0.135 g, 0.53mmol) in dry tetrahydrofuran (9 mL) was added. The reaction mixture washeated at reflux for 2 h. The reaction mixture was cooled to roomtemperature, water (5 mL) was added followed by 10% K₂CO₃ (5 mL). Thereaction mixture was filtered through a pad of Celite and the pad washedwith EtOAc. The filtrate was transferred to a separatory funnel and thelayers were separated. The aqueous layer was extracted with EtOAc andthe combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude material was loaded onto silica andpurified by flash chromatography with a hexanes:EtOAc gradient (100:0 to80:20) to give 0.162 g (88%) of the title compound 171 as an oil. ¹H NMR(400 MHz, DMSO-d₆): δ 0.93 (s, 6 H), 1.31-1.33 (m, 4 H), 2.12-2.19 (m, 4H), 3.81 (s, 3 H), 6.66 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H),7.18 (d, J=8.3 Hz, 2 H), 7.86 (d, J=8.3 Hz, 2 H), 9.36 (s, 1 H).

Step 2:4-[(4,4-Dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoicacid (172)

To a solution of THF (2 mL) and ethanol (2 mL) containing4-[(4,4-dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoicacid methyl ester (171) (0.16 g, 0.457 mmol) was added 1 N NaOH (4 mL).The reaction mixture was heated at 65° C. for 4 h. The reaction mixturewas partially concentrated to remove the EtOH and THF. To the basicaqueous mixture was added 1 N HCl to pH˜1 (according to litmus paper).The acidic aqueous solution was extracted with dichloromethane and theorganic extract washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was triturated with dichloromethane,filtered, and dried to give 0.132 g (85%) of the title compound 172 as awhite powder. ¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (s, 6 H), 1.32 (s, 4 H),2.12-2.19 (m, 4 H), 6.66 (d, J=8.3 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H),7.14 (d, J=8.1 Hz, 2 H), 7.83 (d, J=8 Hz, 2 H), 9.33 (s, 1 H), 12.74 (s,1 H). HRMS (ESI) Calcd for C₂₂H₂₃O₃: 335.1647 (M−H)⁻. Found: 335.1640.

Example 63 (174)

Step 1: 4-(3-Fluoro-4-methoxy-benzoyl)-benzoic acid methyl ester (173)

To an ice-cooled slurry of AlCl₃ (2.01 g, 15.1 mmol) in dichloromethane(10 mL) was slowly added 4-chlorocarbonyl-benzoic acid methyl ester (2g, 10.1 mmol) in dichloromethane (5 mL). The reaction mixture wasstirred for 20 min in the ice bath then 2-fluoroanisole (1.4 mL, 12.1mmol) in dichloromethane (5 mL) was added. The reaction mixture wasstirred at room temperature for 20 h. The reaction mixture was pouredinto ice cold 1 N HCl (10 mL) and the mixture was stirred for 15 min.The reaction mixture was transferred to a separatory funnel and thelayers were separated. The aqueous layer was extracted withdichloromethane and the organic extracts were combined, washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude solid wastriturated with hot hexanes, filtered and washed with hexanes to give0.5 g (17%) of compound 173 as a white powder. ¹H NMR (400 MHz,DMSO-d₆): δ 3.89 (s, 3 H), 3.94 (s, 3 H), 7.32 (t, J=8.5 Hz, 1 H), 7.57(d, J=8.8 Hz, 1 H), 7.59-7.63 (m, 1 H), 7.81 (d, J=8.2 Hz, 2 H), 8.04(s, 1 H), 8.10 (d, J=8.3 Hz, 2 H).

Step 2: 4-[Cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoicacid (174)

AlCl₃ (0.97 g, 7.28 mmol) was added portionwise via an addition funnelto a solution of 4-(3-fluoro-4-methoxy-benzoyl)-benzoic acid methylester (173) (0.50 g, 1.73 mmol) in toluene (8 mL). The reaction mixturewas heated at reflux for 20 h and allowed to cool to RT. Water (10 mL)was slowly added to the reaction mixture. The reaction mixture wastransferred to a separatory funnel and extracted with EtOAc, the organicextract washed with brine, dried over Na₂SO₄, filtered, and concentratedto give a solid. The resulting solid was triturated withdicholormethane. The suspension was filtered, and the filtered solid wasdried to give 0.37 g of the crude product as a mixture of4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid and4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid methyl ester according to ¹HNMR and LCMS (ESI). The crude product was used without furtherpurification. To a slurry of zinc powder (0.67 g, 10.3 mmol) in dry THF(11 mL) was slowly added TiCl₄ (0.55 mL, 4.99 mmol) at RT under anitrogen atmosphere. The reaction mixture was heated at reflux for 2.5h. To the reaction mixture was added a solution of cycloheptanone (0.48mL, 4.05 mmol) and the aforementioned mixture of4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid and4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid methyl ester (0.37 g) in drytetrahydrofuran (11 mL). The reaction mixture was heated at reflux undera nitrogen atmosphere for 2 h. The reaction mixture was cooled to roomtemperature, water (15 mL) was added followed by 10% K₂CO₃(15 mL). Thereaction was filtered through a pad of Celite, and the pad washed withEtOAc. The filtrate was transferred to a separatory funnel and thelayers were separated. The aqueous layer was extracted with EtOAc andthe combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude material was loaded onto silica geland partially purified by flash chromatography with a CH₂Cl₂:MeOHgradient (100:0 to 98:2) to yield the impure title compound (0.15 g) aswell as impure4-[cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoic acidmethyl ester (0.22 g) according to ¹H NMR. The impure benzoic acid waspurified by reverse phase preparative HPLC using a C-18 column and aCH₃CN:H₂O gradient (50:50 to 100:0) with 0.05% TFA as a modifier to give0.072 g (12% based on 4-(3-fluoro-4-methoxy-benzoyl)-benzoic acid methylester) of compound 174 as a yellow amorphous solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.51 (m, 8 H), 2.16 (m, 2 H), 2.18 (m, 2 H), 6.71 (d, J=1.8Hz, 1 H), 6.75-6.88 (m, 2 H), 7.21 (d, J=8 Hz, 2 H), 7.85 (d, J=8.2 Hz,2 H), 9.76 (s, 1 H), 12.84 (s, 1 H). HRMS (ESI) Calcd for C₂₁H₂₀FO₃:339.1396 (M−H)⁻. Found: 339.1411.

Example 64 (177)

Step 1: 4-[(4-Bromo-2-fluoro-phenyl)-cycloheptylidene-methyl]-phenol(175)

To a slurry of Zn powder (3.4 g, 51.5 mmol) in dry tetrahydrofuran (50mL) was slowly added TiCl₄ (2.7 mL, 25.1 mmol) at RT under a nitrogenatmosphere. The reaction mixture was heated at reflux for 2.5 h. To thereaction mixture was added a solution of cycloheptanone (2.4 mL, 20.3mmol) and (4-bromo-2-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (76) (2g, 6.78 mmol) in dry tetrahydrofuran (50 mL). The reaction mixture washeated at reflux for 2 h. The reaction mixture was cooled to roomtemperature, then water (40 mL) was added followed by 10% K₂CO₃ (40 mL).The reaction mixture was filtered through a pad of Celite and the padwashed with EtOAc. The filtrate was transferred to a separatory funneland the layers were separated. The aqueous layer was extracted withEtOAc and the combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude material was loaded ontosilica gel and purified by flash chromatography with a hexanes:EtOAcgradient (100:0 to 90:10) to give 2.24 g (88%) of compound 175. ¹H NMRindicates that the product contains ˜3% cycloheptanone. ¹H NMR (400 MHz,DMSO-d₆): δ 1.43-1.50 (m, 8 H), 2.05-2.08 (m, 2 H), 2.23-2.24 (m, 2 H),6.65 (d, J=8.4 Hz, 2 H), 6.91 (d, J=8.4 Hz, 2 H), 7.14, (t, J=8.1 Hz, 1H), 7.32-7.35 (m, 1 H), 7.44-7.47 (m, 1 H), 9.33 (s, 1 H).

Step 2:3-{4-[Cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl}-acrylicacid ethyl ester (176)

To a solution of4-[(4-bromo-2-fluoro-phenyl)-cycloheptylidene-methyl]-phenol (175) (1.0g, 2.66 mmol) in DMF (27 mL) was added ethyl acrylate (2.9 mL, 26.6mmol), dichlorobis(triphenylphosphine)palladium(II) (0.187 g, 0.266mmol) and Et₃N (2.2 mL, 15.99 mmol). The reaction mixture was heated at100° C. for 20 h. The reaction mixture was cooled to room temperatureand diluted with water (10 mL) and EtOAc (20 mL). The aqueous mixturewas transferred to a separatory funnel and the layers were separated.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was loaded onto silica gel and purifiedby flash chromatography with a hexanes:EtOAc gradient (100:0 to 90:10)to give 0.85 g (81%) of the title compound 176 as an oil. ¹H NMR (400MHz, DMSO-d₆): δ 1.22 (t, J=7.1 Hz, 3 H), 1.48-1.51 (m, 8 H), 2.07-2.10(m, 2 H), 2.25 (s, 2 H), 4.13-4.18 (m, 2 H), 6.61-6.66 (m, 3 H), 6.92(d, J=8.6 Hz, 2 H), 7.20 (t, J=7.8 Hz, 1 H), 7.47 (d, J=6.6 Hz, 1 H),7.56-7.60 (m, 2 H), 9.32 (s, 1 H).

Step 3:3-{4-[Cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl}-acrylicacid (177)

To a solution of3-{4-[cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl)-acrylicacid ethyl ester (176) (0.8 g, 2.15 mmol) in THF (10 mL) and ethanol (10mL) was added 1 N sodium hydroxide (21 mL). The reaction mixture washeated at 65° C. for 2.5 h. The reaction mixture was partiallyconcentrated to remove the EtOH and THF. To the basic aqueous mixturewas added 1 N HCl to pH˜1 (according to litmus paper). The acidicaqueous solution was extracted with dichloromethane and the organicextract washed with brine, dried over Na₂SO₄, filtered and concentrated.The crude material was triturated with dichloromethane, filtered anddried to give 0.065 g (10%) of compound 177 as a white powder. ¹H NMR(400 MHz, DMSO-d₆): δ 1.51 (b, 8 H), 2.09 (m, 2 H), 2.25 (m, 2 H), 6.52(d, J=16.1 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H),7.19 (t, J=7.8 Hz, 1 H), 7.43-7.49 (m, 1 H), 7.51-7.53 (m, 2 H), 9.32(s, 1 H), 12.43 (s, 1 H). HRMS (ESI) Calcd for C₂₃H₂₂FO₃: 365.1553(M−H)⁻. Found: 365.1543.

Example 65 (181)

Step 1: (4-Amino-phenyl)-(4-methoxy-phenyl)-methanone (178)

Sodium dithionite (8.1 g, 46.6 mmol) was added to a slurry of4-methoxy-4-nitrobenzophenone (3 g, 11.66 mmol) in 95% ethanol (73 mL)and heated at reflux for 20 h. The reaction mixture was cooled to roomtemperature and concentrated to remove the ethanol. The concentratedmaterial was partitioned between EtOAc and water and the layers wereseparated. The aqueous layer was extracted with EtOAc, and the organicextracts were combined, washed with brine, dried over Na₂SO₄, filtered,and concentrated to give an oil, which solidified upon standing. Thesolid was purified by flash chromatography with a CH₂Cl₂:MeOH gradientof (100:0 to 99:1) to give 1.72 g (65%) of the title compound 178 as anoff white powder. ¹H NMR (400 MHz, DMSO-d₆): δ 3.81 (s, 3 H), 6.04 (s, 2H), 6.57 (d, J=8.6 Hz, 2 H), 7.02 (d J=8.8 Hz, 2 H), 7.47 (d, J=8.6 Hz,2 H), 7.60 (d, J=8.8 Hz, 2 H).

Step 2: N-[4-(4-Methoxy-benzoyl)-phenyl]-methanesulfonamide (179)

Methanesulfonyl chloride (0.15 mL, 1.94 mmol) was slowly added to anice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone(178) (0.4 g, 1.76 mmol) and pyridine (0.16 mL, 1.94 mmol) in drydichloromethane (5 mL). The reaction mixture was stirred at roomtemperature for 20 h then diluted with EtOAc and water. The layers wereseparated and the aqueous layer was extracted with EtOAc. The organicextracts were combined, washed with brine, dried over Na₂SO₄, filteredand concentrated to give 0.5 g (93%) of compound 179 as a solid. ¹H NMR(400 MHz, DMSO-d₆): δ 3.11 (s, 3 H), 3.84 (s, 3 H), 7.06 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.6 Hz, 2 H), 7.68-7.72 (m, 4 H), 10.31 (s, 1 H).

Step 3:N-{4-[(4-Methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide(180)

Titanium tetrachloride (0.66 mL, 6.06 mmol) was slowly added to a slurryof Zn powder (0.81 g, 12.4 mmol) in dry THF (14 mL). The reactionmixture was heated at reflux for 2.5 h. A solution of3,3,5,5-tetramethyl-cyclohexanone (0.86 mL, 4.91 mmol) andN-[4-(4-methoxy-benzoyl)-phenyl]-methanesulfonamide (9) (0.5 g, 1.64mmol) in dry THF (14 mL) was added to the reaction mixture and heated atreflux for another 2 h. The reaction mixture was cooled to roomtemperature and diluted with water (10 mL) followed by 10% K₂CO₃ (10mL).The reaction mixture was filtered through a pad of Celite and thepad washed with EtOAc. The filtrate was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was extractedwith EtOAc and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The crude material was loadedonto silica gel and purified by flash chromatography with ahexanes:EtOAc gradient (100:0 to 60:40) to give 0.5 g (71%) of the titlecompound 180 as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 0.87 (s, 6H), 0.87 (s, 6 H), 1.24 (s, 2 H), 1.88-1.89 (m 4 H), 2.95 (s, 3 H), 3.70(s, 3 H), 6.83 (d, J=8.8 Hz, 2 H), 7.03 (d, J=8.6 Hz, 2 H), 7.08 (m, 4H), 9.66 (s, 1 H).

Step 4:N-{4-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide(181)

To a solution ofN-{4-[(4-methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide(180) (0.25 g, 0.585 mmol) in dry dichloromethane (20 mL) was slowlyadded BBr₃ (1 N in dichloromethane) (1.75 mL, 1.75 mmol) at −5 to 0° C.The reaction mixture was stirred at −5 to 0° C. under nitrogen for 3 h.The reaction mixture was poured onto ice and stirred for severalminutes. The quenched reaction mixture was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was extractedwith EtOAc and the organic extracts were combined, washed with brine,dried over MgSO₄, filtered, and concentrated to give an off white solid.The solid was triturated with hexanes followed by dichloromethane. Theproduct was filtered, washed with methanol, and dried to give 0.174 g(72%) of compound 181 as a white powder. ¹H NMR (400 MHz, DMSO-d₆): δ0.86 (s, 12 H), 1.23 (s, 2 H), 1.86 (s, 2 H), 1.89 (s, 2 H), 2.94 (s, 3H), 6.64 (d, J=8.6 Hz, 2 H), 6.90 (d, J=8.5 Hz, 2 H), 7.06 (s, 2 H),7.07 (s, 2 H), 9.25 (s, 1 H), 9.64 (s, 1 H). HRMS (ESI) calcd forC₂₄H₃₀NO₃S: 412.1946 (M−H)⁻. Found: 412.1942.

Example 66 (184)

Step 1: N-[4-(4-Methoxy-benzoyl)-phenyl]-benzenesulfonamide (182)

Benzenesulfonyl chloride (0.26 mL, 2.03 mmol) was slowly added to anice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone(178) (0.42 g, 1.85 mmol) and pyridine (0.16 mL, 2.03 mmol) in drydichloromethane (5 mL). The reaction mixture was stirred at roomtemperature for 20 h then partitioned between EtOAc and water. Thelayers were separated and the aqueous layer was extracted with EtOAc.The organic extracts were combined, washed with brine, dried overNa₂SO₄, filtered, and concentrated to give a solid. The solid wasrecrystallized from hot dichloromethane and methanol to give 0.451 g(66%) of the title compound 182. ¹H NMR (400 MHz, DMSO-d₆): δ 3.82 (s, 3H), 7.03 (d, J=8.8 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H), 7.57-7.65 (m, 7H), 7.84 (d, J=7.3 Hz, 2 H), 10.87 (s, 1 H).

Step 2:N-{4-[(4-Methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-benzenesulfonamide(183)

Titanium tetrachloride (0.50 mL, 4.53 mmol) was slowly added to a slurryof zinc powder (0.61 g, 9.31 mmol) in dry tetrahydrofuran (10 mL). Thereaction mixture was heated at reflux for 2.5 h. A solution of3,3,5,5-tetramethyl-cyclohexanone (0.64 mL, 3.67 mmol) andN-[4-(4-methoxy-benzoyl)-phenyl]-benzenesulfonamide (182) (0.45 g, 1.22mmol) in dry tetrahdyrofuran (10 mL) was added to the reaction mixtureand heated at reflux for another 2 h. The reaction mixture was cooled toroom temperature and diluted with water (10 mL) followed by 10% K₂CO₃(10 mL). The reaction mixture was filtered through a pad of Celite andthe pad washed with EtOAc. The filtrate was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was extractedwith EtOAc and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The crude material was purifiedby flash chromatography on silica gel with a hexanes:EtOAc gradient(100:0 to 55:45) to give 0.48 g (80%) of compound 183 as a white powder.¹H NMR (400 MHz, DMSO-d₆): δ 0.81 (s, 6 H), 0.84 (s, 6 H), 1.21 (s, 2H), 1.75, (s, 2 H), 1.85 (s, 2 H), 3.68 (s, 3 H), 6.79 (d, J=8.6 Hz, 2H), 6.95-6.98 (m, 6 H), 7.47-7.50 (m, 2 H), 7.55-7.58 (m, 1 H), 7.69 (d,J=7.3 Hz, 2 H), 10.17 (s, 1 H).

Step 3:N-{4-[(4-Hydroxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-benzenesulfonamide(184)

To a solution ofN-{4-[(4-methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-benzenesulfonamide(183) (0.24 g, 0.490 mmol) in dry dichloromethane (17 mL) was slowlyadded BBr₃ (1 N in dichloromethane) (1.47 mL, 1.47 mmol) at −5 to 0° C.The reaction mixture was stirred under nitrogen at −5 to 0° C. over 3 h.The reaction mixture was poured onto ice and stirred for severalminutes. The quenched reaction mixture was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was extractedwith EtOAc and the organic layers were combined, washed with brine,dried over MgSO₄, filtered, and concentrated to give an oil. The crudeoil was purified by reverse phase preparative HPLC using a C-18 columnand a CH₃CN:H₂O gradient (75:25 to 100:0) with 0.05% TFA as a modifierto give 0.087 g (37%) of the title compound 184 as an off white powder.¹H NMR (400 MHz, DMSO-d₆): δ 0.80 (s, 6 H), 0.84 (s, 6 H), 1.20 (s, 2H), 1.73 (s, 2 H), 1.85 (s, 2 H), 6.61 (d, J=8.6 Hz, 2 H), 6.84 (d,J=8.4 Hz, 2 H), 6.94 (s, 4 H), 7.48-7.50 (m, 2 H), 7.54-7.58 (m, 1 H),7.68-7.70 (m, 2 H), 9.23 (s, 1 H), 10.16 (s, 1 H). HRMS (ESI) Calcd forC₂₉H_(32N)O₃S: 474.2103 (M−H)⁻. Found: 474.2098.

Example 67 (188)

Step 1: (4-Bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185)

To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (3.00 g, 12.6mmol) and anisole (1.65 mL, 1.65 g, 15.2 mmol, 1.20 eq) in DCM (30 mL)at −5° C. was added, portion-wise, over 5 minutes, AlCl₃ (2.54 g, 19.0mmol, 1.50 eq) as a powder. The reaction was stirred at −5° C. for 2 h.The reaction was poured onto a mixture of 1 N HCl (100 mL) and ice (200g) and stirred for 1 h. The DCM layer washed with saturated aq. NaHCO₃(100 mL) and brine (100 mL) then dried (MgSO₄) and concentrated. Theresulting white solid was triturated with ˜100 mL hexanes, filtered andair-dried overnight to afford 3.26 g (83%) of compound 185. ¹H NMR (400MHz, DMSO-d₆): δ 3.87 (s, 3 H), 7.11 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9Hz, 1H), 7.64 (d, J=8.9 Hz, 1 H), 7.78 (d, J=8.9 Hz, 2H), 7.91 (t, J=7.1Hz, 1H).

Step 2: (4-Bromo-3-fluorophenyl)(4-hydroxyphenyl)methanone (186)

To a stirred solution of(4-bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185) (3.20 g,10.4 mmol) in benzene (80 mL) was slowly added AlCl₃ (5.91 g, 44.2 moL.,4.3 eq) via a powder addition funnel under a nitrogen atmosphere at roomtemperature. The stirred reaction mixture was heated at reflux for 3 hunder a nitrogen atmosphere. The reaction mixture was allowed to cool toroom temperature and then poured onto a mixture of 1 N HCl (150 mL) andice (300 g). The quenched reaction mixture was transferred to aseparatory funnel and EtOAc (200 mL) added. The organic phase wasseparated and the aqueous phase was extracted with EtOAc. The organicphase washed with brine (200 mL), dried over MgSO₄, filtered, and thefiltrate was concentrated in vacuo to give 3.44 g of a brown solid.Crystallization from toluene yielded 2.68 g (88%) of the title compound186 as a brown crystalline solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.91 (d,J=8.7 Hz, 2 H), 7.43 (d, J=8.2 Hz, 1 H), 7.61 (d, J=8.2 Hz, 1 H), 7.69(d, J=8.7 Hz, 2 H), 7.89 (t, J=7.1 Hz, 1H), 10.54 (s, 1 H).

Step 3: 4-[(4-Bromo-3-fluorophenyl)(cycloheptylidene)methyl]phenol (187)

To a stirred suspension of zinc powder (0.90 g, 13.8 mmoL) in anhydrousTHF (20 mL) was slowly added TiCl₄ (0.75 mL, 1.3 g, 6.8 mmoL) viasyringe at RT under a nitrogen atmosphere. (Note: significant fumingoccurred upon addition of TiCl₄.) The reaction mixture was heated atreflux with stirring under nitrogen for 2.25 h. A solution of(4-bromo-3-fluorophenyl)(4-hydroxyphenyl)methanone (186) (0.50 g, 1.7mmoL) and cycloheptanone (0.6 mL, 0.57 g, 5.09 mmoL) in THF (10 mL) wasadded to the reaction mixture via syringe. The reaction mixture washeated at reflux for 2 h. The oil bath was removed and the reactionmixture was allowed to cool at RT. To the reaction mixture was added H₂O(10 mL) followed by 10% K₂CO₃ (10 mL). The quenched reaction mixture wasfiltered through a pad of Celite with the aid of EtOAc and H₂O. The padwashed with EtOAc and the filtrate was transferred to a separatoryfunnel. The layers were separated and the organic phase was allowed tostand at RT over the weekend. The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated in vacuo to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give 0.48 g(75%) of compound 187 as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.50 (m, 8 H), 2.20 (m, 4 H), 6.67 (d, J=8.4 Hz, 2 H), 6.88 (dd, J=1.9Hz, 8.3 Hz, 1 H), 6.92 (d, J=8.4 Hz, 2 H), 7.08 (dd, J=1.8 Hz, 10.0 Hz,1 H), 7.59 (t, J=7.9 Hz, 1 H), 9.33 (s, 1 H). LRMS (ESI): m/z 373(M−H)⁻.

Step 4:(2E)-3-{4-[Cycloheptylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoicacid (188)

To a round-bottomed flask were added4-[(4-bromo-3-fluorophenyl)(cycloheptylidene)methyl]phenol (187) (0.21g, 0.56 mmoL), tert-butylacrylate (0.25 mL, 0.22 g, 1.7 mmoL),palladium(II)acetate (0.023 g, 0.10 mmoL), triethylamine (0.22 mL, 0.16g, 1.6 mmoL), P(o-tolyl)₃ (0.071 g, 0.23 mmol) and anhydrous CH₃CN (10mL). The stirred reaction mixture was heated at 75° C. under a nitrogenatmosphere for 15 h. The oil bath was removed and the reaction mixturewas allowed to cool at RT. Thin layer chromatography (hexanes:EtOAc(9:1)) indicated that only starting material was present. The reactionmixture was concentrated in vacuo to give an orange oil. To the oil wereadded tert-butylacrylate (0.82 mL, 0.72 g, 5.6 mmoL), triethylamine(0.40 mL, 0.29 g, 2.87 mmoL),dichlorobis(triphenylphosphine)palladium(II) (0.091 g, 0.13 mmoL), andanhydrous DMF (5 mL). The stirred reaction mixture was heated overnightat 110° C. under a nitrogen atmosphere. The oil bath was removed and thedark brown reaction mixture was allowed to cool at RT. The reactionmixture was partitioned between EtOAc and H₂O. The layers were separatedand the organic phase was dried over MgSO₄, filtered, and the filtratewas concentrated in vacuo to give the crude acrylate ester. The acrylateester intermediate was partially purified by flash chromatography onsilica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give 0.171g of impure1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate.To a stirred solution of the impure tert-butylacrylate ester (0.17 g) inCH₂Cl₂ (4 mL) was added trifluoroacetic acid (2 mL) at RT. The reactionmixture was stirred at RT under a nitrogen atmosphere for 2.75 h. Thereaction mixture was concentrated in vacuo to give the crude acrylicacid. The crude product was purified by reverse phase preparative HPLCusing a C-18 column and a CH₃CN:H₂O gradient (75:25 to 100:0) with 0.05%TFA as a modifier to give 0.080 g (39% over two steps) of compound 188as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.50 (m, 8 H), 2.21(m, 4 H), 6.51 (d, J=16.1 Hz, 1 H), 6.67 (d, J=8.4 Hz, 2 H), 6.92 (d,J=8.2 Hz, 2H), 6.97 (m, 2 H), 7.58 (d, J=16.1 Hz, 1 H), 7.72 (t, J=8.2Hz, 1 H), 9.32 (s, 1 H), 12.50 (br s, 1 H). HRMS (ESI) Calcd forC₂₃H₂₂O₃F: 365.1553 (M−H)⁻. Found: 365.1570.

Example 68 (191)

Step 1: 4,4′-(Cycloheptylidenemethanediyl)diphenol (189)

To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300mL) was slowly added TiCl₄ (12.5 mL, 0.115 mol) via a syringe at roomtemperature under a nitrogen atmosphere. The reaction mixture was heatedat reflux for 1 h. A solution of bis(4-hydroxyphenyl)methanone (4.9 g,0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 mL) wasadded to the reaction mixture. The reaction mixture was heated at refluxwith stirring under a nitrogen atmosphere for an additional 2 h. Thereaction mixture was allowed to cool to room temperature. The reactionmixture was poured into a 10% aqueous K₂CO₃ (1 L). The reaction mixturewas filtered through a pad of Celite and the pad washed with EtOAc. Thefiltrate was transferred to a separatory funnel and the layers wereseparated. The aqueous phase was further extracted with EtOAc (4×250mL). The combined organic phase washed with brine (2×100 mL), dried(Na₂SO₄), filtered, and then concentrated under reduced pressure to givethe crude product as a gold-yellow oil. The crude product was purifiedby flash chromatography on silica gel with hexanes:EtOAc (100:0 to50:50) as an eluent to afford 6.75 g (99%) of the title compound 189 asa white solid. ¹H NMR (DMSO-d₆): δ 9.21 (s, 2H), 6.84 (d, J=6.3 Hz, 4H),6.63 (d, J=6.3 Hz, 4H), 2.19 (br s, 4H), 1.48 (br s, 8H). LCMS (ESI):m/z 294 (M+H)⁺.

Step 2:Ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate(190)

To a stirred suspension of 4,4′-(cycloheptylidenemethanediyl)diphenol(189) (1.176 g, 4 mmol), K₂CO₃ (0.692 g, 5 mmol), and acetone (100 mL)was added bromoEtOAc (0.664 mL, 6 mmol) under a nitrogen atmosphere atroom temperature. The reaction mixture was refluxed for 3 h then cooledto RT and filtered. The filtrate was concentrated under reduced pressureand the crude product purified by flash chromatography on silica gelwith hexanes and EtOAc (19:1 to 4:1) to afford 0.440 g (29%) of thetitle compound 190 as a white solid and 0.408 g (22%) of dialkylatedproduct as a white solid. Around 0.40 g of starting material 189 wasalso recovered. Data forethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate: ¹HNMR (300 MHz, CDCl₃): δ 7.28 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.02 (d,J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 4.70 (s,1H), 4.60 (s, 2H), 4.28 (q, J=6.9 Hz, 2H), 2.31 (br s, 4H), 1.58 (br s,8H), 1.31 (t, J=7.2 Hz, 3H). LCMS (ESI): m/z 403 (M+Na)⁺.

Step 3: ({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)aceticacid (191)

Ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate(190) (0.20 g, 0.53 mmol) was dissolved in THF and EtOH (1:1, 6 mL). Tothe above solution was added 1 N NaOH (2.5 mL) at room temperature. Thereaction was heated at 70° C. with stirring for 0.5 h and then cooled atRT. Reaction mixture was acidified with 20% aqueous HCl, and thenextracted with EtOAc. The organic layer washed with brine, dried(Na₂SO₄), and concentrated under reduced pressure to afford the crudeproduct. The product was purified by flash column chromatography withchloroform and methanol (9:1 to 4:1) as an eluent to give 0.182 g ofcompound 191 as an off-white solid. mp 170-171° C. ¹H NMR (300 MHz,DMSO-d₆): δ 12.92 (s, 1H), 9.25 (s, 1H),

d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.66(d, J=8.4 Hz, 2H), 4.62 (s, 2H), 2.22 (br s, 4H), 1.5 (br s, 8H). LCMS(ESI): m/z 375.08 (M+Na)⁺. Anal. Calcd for C₂₂H₂₄O₄: C, 74.98; H, 6.86;Found: C, 73.05; H, 6.74.

Example 69 (195)

Step 1: {(4-Bromophenyl)[3-(methyloxy)phenyl]methylidene}cycloheptane(192)

The general McMurry coupling procedure, described for 14 was followed.Coupling between (4-bromophenyl)[3-(methyloxy)phenyl]methanone andcycloheptanone afforded 2.1 g (82%) of compound 192 as a white solid. ¹HNMR (300 MHz, CDCl₃): δ 7.41 (d, J=8.4 Hz, 2H), 7.22 (dd, J=₁ 15.6 Hz,J₂=7.8 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.77-6.71 (m, 4H).

Step 2: 3-[(4-Bromophenyl)(cycloheptylidene)methyl]phenol (193)

To a cold (5° C.) solution of{(4-bromophenyl)[3-(methyloxy)phenyl]methylidene}cycloheptane (192)(0.557 g, 1.5 mmol) in CH₂Cl₂ (50 mL) was added BBr₃ (0.425 mL, 4.5mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C.for 4 h and then carefully poured into water (100 mL). The layers wereseparated and the aqueous layer was further extracted with CH₂Cl₂ (2×50mL) and the combined organic layer dried (Na₂SO₄). Concentration andpurification by flash column chromatography gave 0.44 g (82%) ofcompound 193 as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.41 (d,J=8.4 Hz, 2H), 7.17 (dd, J₁=7.8 Hz, J₂=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz,2H), 6.74 (br d, J=7.5 Hz, 1H), 6.69 and 6.67 (dd, J₁=2.4 Hz, J₂=8.1 Hz,1H), 6.62 (app t, J=1.8 Hz), 4.71 (s, 1H), 2.32 (br, m, 4H), 1.59 (br s,8H).

Step 3:1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoate(194)

Heck reaction with{(4-bromophenyl)[3-(methyloxy)phenyl]methylidene}cycloheptane (193)(0.420 g, 1.47 mmol) and ethyl acrylate (as described in Example 6, Step2) followed by standard work-up purification gave 0.26 g (47%) ofcompound as 194 an off-white foam. ¹H NMR (300 MHz, CDCl₃): δ 7.56 (d,J=15.9 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.19-7.15 (m, 3H), 6.76 (br d,J=7.5 Hz, 1H), 6.7 and 6.68 (br dd, J₁=2.4 Hz, J₂=8.1 Hz, 1H), 6.4 (s,1H), 6.33 (d, J=15.9 Hz, 1H), 4.86 (s, 1H), 2.33 (br s, 4H), 1.60 (s,8H), 1.55 (s, 9H). LCMS (ESI): m/z 405 (M−H)⁻.

Step 4:(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoicacid (195)

To a cold (5° C.) solution of1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoate(194) (0.200 g, 0.49 mmol) in CH₂Cl₂ (8 mL) was added TFA (2 mL). Theresultant mixture was stirred for 3 h at RT. The reaction mixture wasconcentrated under reduced pressure and the crude product. purified bysilica gel chromatography using n-hexanes:EtOAc (4:1 to 3:2) as aneluent to afford 0.155 g (90%) of compound 195 as an off-white foam. ¹HNMR (300 MHz, CD₃OD): δ 7.65 (d, J=15.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H),7.21 (d, J=7.8 Hz, 2H), 7.10 (app t, J=7.5 Hz, 1H), 6.32 (br d, J=8.7Hz, 3H), 6.45 (d, J=15.9 Hz, 1H). 2.33 (br s, 4H), 1.61 (br s, 8H). LCMS(ESI): m/z 347 (M−H)⁻.

Example 70 (199)

Step 1: (4-Bromo-3-fluorophenyl)(3-hydroxyphenyl)methanone (196)

The demethylation procedure described for 2 was employed. To a stirredsolution of (4-bromo-3-fluorophenyl)[3-(methyloxy)phenyl]methanone (1.0g, 2.5 mol) in toluene (50 mL) was slowly added AlCl₃ (1.3 g, 9.7 mol)via a powder addition funnel under a nitrogen atmosphere at roomtemperature. The stirred reaction mixture was heated at reflux for 3 h.The reaction mixture was allowed to cool to room temperature and thenpoured into 10% aqueous HCl (200 mL). Standard work-up yielded 0.935 g(100%) of the title compound 196 as a tan solid. ¹H NMR (300 MHz,CDCl₃): δ 7.71 and 7.68 (dd, J₁=6.6 Hz, J₂=6.6 Hz, 1 H), 7.60 and 7.57(dd, J₁=8.7 Hz, J₂=1.5 Hz, 1H), 7.50 and 7.47 (dd, J₁=8.1 Hz, J₂=1.2 Hz,1H), 7.41-7.31 (m 3H), 7.15 and 7.13 (dd, J₁=7.8 Hz, J₂=1.8 Hz, 1H),5.93 (s, 1H).

Step 2: 3-[(4-Bromo-3-fluorophenyl)(cycloheptylidene)methyl]phenol (197)

The general McMurry protocol, described for 14 was followed. Reaction of(4-bromo-3-fluorophenyl)(3-hydroxyphenyl)methanone (196 (0.860 g, 2.3mmol) and cycloheptanone (0.814 mL, 6.87 mmol) afforded 0.80 g, (93%) ofthe title compound 197 as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.89(app t, J=7.5 Hz, 1H), 7.17 (app t, J=7.8 Hz, 1H), 6.96 and 6.92 (dd,J₁=9.6 Hz, J₂=1.8 Hz, 1H), 6.86 and 6.84 (dd, J₁=8.1 Hz, J₂=1.8 Hz, 1H),6.73 (app br d, J=8.1 Hz, 1H), 6.70 and 6.68 (dd, J₁=8.4 Hz, J₂=2.4 Hz,1H), 6.61 (app t, J=1.8 Hz, 1H), 4.86 (s, 1H), 2.31 (br s, 4H), 1.59 (brs, 8H).

Step 3:1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate(198)

The general Heck protocol, described for 15 was followed. Heck couplingbetween 3-[(4-bromo-3-fluorophenyl)(cycloheptylidene)methyl]phenol (197)(0.800 g, 2.13 mmol) and ethyl acrylate afforded 0.460 g, (51%) of thetitle compound 198 as an off-white foam. ¹H NMR (300 MHz, CDCl₃): δ 7.68(d, J=16.2 Hz, 1H), 7.41 (app t, J=8.1 Hz, 1H), 7.18 (app t, J=7.8 Hz,1H), 6.97 and 6.94 (app br, dd, J₁=8.1 Hz, 1H), 6.93 and 6.88 (br dd,J₁=11.4 Hz, 1H), 6.73 (br d, J=7.50 Hz, J=7.5 Hz, 1H), 6.72 and 6.69(app J₁=8.1 Hz, J₂=2.4 Hz, 1H), 6.70 and 6.68 (dd, J₁=8.4 Hz, J₂=2.4 Hz,1H), 6.63 (app t, J=1.8 Hz, 1H), 6.42 (d, J=15.9 Hz, 1H), 4.97 (s, 1H),2.33 (br s, 4H), 1.61 and 1.59 (br s, 8H), 1.55 (br s, 9H). LCMS (ESI):m/z 421 (M−H)⁻.

Step 4: (2E)-3-{4-[Cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoic acid (199)

The general hydrolysis procedure, described for 195 was followed. Thus,1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate(198) (0.380 g, 0.9 mmol) in CH₂Cl₂ was treated with TFA to afford 0.305g (92%) of the title compound as an off-white foam. ¹H NMR (300 MHz,CD₃OD): δ 7.76 (d, J=15.9 Hz, 1H), 7.59 (appt, J=7.8 Hz, 1H), 7.18 (appt, J=7.8 Hz, 1H), 7.04 (br d, J=8.1 Hz, 1H), 6.94 (br d, J=11.7 Hz, 1H),6.67-6.60(m, 3H), 6.56 (d, J=16.2 Hz, 1H), 2.34 (br s, 4H), 1.62 (br s,8H). LCMS (ESI): m/z 365 (M−H)⁻. Anal. Calcd for C₂₃H₂₃FO₃.1.5H₂O, C,70.38; H, 6.63; F, 4.84; Found: C, 69.96; H, 5.95; F, 4.73.

Example 71 (201)

Step 1: 4-[(4-Bromophenyl)(cycloheptylidene)methyl]phenol (200)

The general McMurry coupling protocol, described for 14 was followed.Reaction of (4-bromophenyl)(4-hydroxyphenyl)methanone (2.77 g, 10 mmol),and cycloheptanone (3.6 mL, 30 mmol) afforded 2.795 g (78%) of the titlecompound 200 as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.41 (d,J=8.1 Hz, 2H), 7.04 (d, J=6.3 Hz, 2H), 7.01 (d, J=6.3 Hz, 2H), 6.76 (d,J=8.4 Hz, 2H), 4.74 (s, 1H), 2.32 (m, 4H), 1.59 (s, 8H).

Step 2: 4-{cycloheptylidene[4-(3-furanyl)phenyl]methyl}phenol (201)

A round-bottom flash was charged with4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (200) (1.0 g, 2.8mmol), Pd(PPh₃)₄, (0.323 g, 0.28 mmol), 3-furanylboronic acid (0.627 g,5.6 mmol), aqueous 2 M Na₂CO₃, (1.2 g, 4.7 mL, 11.2 mmol), and DME (15mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 5h. Reaction mixture was cooled at room temperature, diluted with Et₂O(30 ml) and filtered. The filtrate was diluted with EtOAc (100 mL),washed with brine, dried (Na₂SO₄) and concentrated under reducedpressure to afford the crude product. The product was purified by silicagel chromatography using n-hexanes:EtOAc (19:1 to 4:1) as an eluent togive 0.887 g (92%) of the title compound 201 as a white solid. ¹H NMR(300 MHz, CDCl₃): δ 7.73 (s, 1H), 7.48 (t, J=1.5 Hz, 1H), 7.42 (d, J=8.1Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS(ESI): m/z 343 (M−H)⁻. Anal. Calcd for C₂₄H₂₄O₂, C, 83.69; H, 7.02;Found: C, 82.69; H, 7.06.

Example 72 (202)

Step 1: 4-{Cycloheptylidene[4-(2-furanyl)phenyl]methyl}phenol (202)

The round-bottom flask was charged with4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28mmol), PdCl₂(PPh₃)₂, (0.020 g, 0.028 mmol), 2-furanylboronic acid (0.063g, 0.56 mmol), aqueous 2 M Na₂CO₃, (0.06 g, 0.56 mmol), and THF/H₂Omixture (4:1, 5 mL) under a nitrogen atmosphere. The reaction mixturewas refluxed for 10 h. Reaction mixture was cooled to room temperature,diluted with Et₂O (10 mL) and filtered. The filtrate was diluted withEtOAc (30 mL), washed with brine, dried (Na₂SO₄), and concentrated underreduced pressure to afford the crude product. The product was purifiedby silica gel chromatography using hexanes:EtOAc (19:1 to 4:1) as aneluent to give 0.0.42 g (44%) of compound 202 as a white solid. ¹H NMR(300 MHz, DMSO-d₆): δ 69.28 (s, 1H), 7.70 (br s, 1H), 7.59 (d, J=6.0 Hz,2H), 7.12 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz,1H), 6.66 (d, J=6.3 Hz, 1H), 6.55 (br s, 1H), 2.37 (br s, 4H), 1.62 (brs, 8H). LCMS (ESI): m/z 343 (M−H)⁻.

Example 73 (203)

Step 1: 4-{cyclooctylidene[4-(2-furanyl)phenyl]methyl}phenol (203)

The procedure described for 202 was employed. A round-bottomed flask wascharged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49)(0.150 g, 0.404 mmol), PdCl₂(PPh₃)₂, (0.028 g, 0.40 mmol),2-furanylboronic acid (0.090 g, 0.80 mmol), Na₂CO₃ (0.086 g, 0.808mmol), and THF/H₂O (4:1, 5 mL). The reaction mixture was refluxed for 10h. Standard workup and purification by flash silica gel chromatographyprovided 110 mg (76%) of the title compound 203 as a white solid. ¹H NMR(300 MHz, DMSO-d₆): δ 9.27 (s, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.59 (d,J'6.0 Hz, 2H), 7.15 (d, J=6.3 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.86 (d,J=2.4 Hz, 1H), 6.67 (d, J=6.3 Hz, 1H), 6.55 and 6.54 (dd, J₁=2.4 Hz,J₂=1.2 Hz, 1H), 2.48-2.47 (m, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H).2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 357 (M−H)⁻.

Example 74 (204)

Step 1: 4-{Cyclooctylidene[4-(3-furanyl)phenyl]methyl}phenol (204)

The procedure described for 202 was used. A round-bottomed flask wascharged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49)(0.150 g, 0.404 mmol), PdCl₂(PPh₃)₂, (0.028 g, 0.40 mmol),3-furanylboronic acid (0.090 g, 0.80 mmol), Na₂CO₃ (0.086 g, 0.808mmol), and THF/H₂O (4:1, 5 mL). The reaction mixture was refluxed for 10h. Upon usual work-up and purification by flash silica gelchromatography provided 0.110 g (76%) of compound 204 as a white solid.¹H NMR (300 MHz, DMSO-d₆): δ 9.29 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H),7.50 (d, J=6.00 Hz, 2H), 7.11 (d, J=6.00 Hz, 2H), 6.94 (d, J=6.3 Hz,2H), 6.89 (s, 1H), 6.67 (d, J=6.3 Hz, 2H), 2.19 (br s, 4H), 1.60 (br s,2H), 1.50-1.45 (m, 8H). LCMS (ESI): m/z 359 (M+H)⁺.

Example 75 (205)

Step 1:4-{cyclooctylidene[4-(3,5-dimethyl-4-isoxazolyl)phenyl]methyl}phenol(205)

The procedure described for 202 was used. A round-bottomed flask wascharged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49)(0.150 g, 0.404 mmol), PdCl₂(PPh₃)₂, (0.028 g, 0.40 mmol),(3,5-dimethyl-4-isoxazolyl)boronic acid (0.113 g, 0.80 mmol), Na₂CO₃(0.086 g, 0.808 mmol), and THF/H₂O (4:1, 5 mL). The reaction mixture wasrefluxed for 10 h. Standard workup and purification by flash silica gelchromatography provided 0.120 g (77%) of the title compound 205 as anoff-white solid. ¹H NMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 7.30 (d,J=6.00 Hz, 2H), 7.21 (d, J=6.30 Hz, 2H), 6.96 (d, J=6.0 Hz, 2H), 6.69(d, J=6.0 Hz, 2H), 2.37 (br s, 3H), 2.19 (s, 7H), 2.60 (br s, 2H), 1.50(br s, 8H). LCMS (ESI): m/z 386 (M−H)⁻.

Example 76 (206)

Step 1:4-{cycloheptylidene[4-(3,5-dimethyl-4-isoxazolyl)phenyl]methyl}phenol(206)

The procedure described for 202 was followed. A round-bottomed flask wascharged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9)(0.100 g, 0.28 mmol), PdCl₂(PPh₃)₂, (0.020 g, 0.028 mmol),(3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na₂CO₃(0.060 g, 0.56 mmol), and THF/H₂O (5 mL, 4:1). The reaction mixture wasrefluxed for 10 h. Standard workup and purification by flash silica gelchromatography provided 0.120 g (78%) of the title compound 206 as anoff-white solid. ¹H NMR (300 MHz, CDCl₃): δ 9.28 (s, 1H), 7.28 (d,J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d,J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H).LCMS (ESI): m/z 372 (M−H)⁻.

Example 77 (208)

Step 1: 4-{Cycloheptylidene[4-(methyloxy)phenyl]methyl}benzonitrile(207)

The general McMurry protocol, described for 14 was employed. Thecoupling was conducted between cycloheptanone (1.5 mL, 12.64 mmol), and4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile (1.0 g, 4.2 mmol) toafford 0.750 g (56%) of the title compound 207 as a white solid. IR(film): 2920, 2225, 1603, 1508, 1242, 825, cm¹. ¹H NMR (300 MHz, CDCl₃):δ 7.58 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz,2H), 6.84 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.36 (br s, 2H), 2.29 (br s,2H), 1.60 (s, 8H).

Step 2: 4-[cycloheptylidene(4-hydroxyphenyl)methyl]benzonitrile (208)

To a cold (5° C.) solution of4-{cycloheptylidene[4-(methyloxy)phenyl]methyl}benzonitrile (207) (0.300g, 0.94 mmol) in CH₂Cl₂ (20 mL) was added BBr₃ (0.358 mL, 3.79 mL). Theresultant reaction mixture was stirred between 5° C. and 20° C. for 3 h.Reaction mixture was poured into water (125 mL) and then extracted withCH₂Cl₂ (3×50 mL). The combined organic layer was dried and concentratedunder reduced pressure to afford the crude product. The product waspurified by flash column chromatography to give 0.245 g (86%) ofcompound 208 as a white solid. mp 110-111° C. IR (film): 3391, 2921,2852, 2229, 1609, 1509, 1213, 829, 731 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ7.57 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H),6.79 (d, J=8.4 Hz, 2H), 4.97 (br s, 1H), 2.35 (br s, 2H), 2.29 (br s,2H), 1.60 (br s, 8H). LCMS (ESI): m/z 302 (M−H)⁻. Anal. Calcd forC₂₁H₂₁NO, C, 83.13; H, 6.98; N, 4.62; Found: C, 83.13; H, 6.96; N, 4.62.

Example 78 (210)

Step 1:4-[[4-(Methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile(209)

The general McMurry protocol, described for 14 was used. The reactionwas conducted between 4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile(1.00 g, 4.21 mmol) and 3,3,5,5-tetramethylcyclohexanone (1.95 g, 12.64mmol) to afford 0.760 g (50%) of the title compound 209 as a whitesolid. ¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.1Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 3.81 (s, 3H),2.01 (s, 2H), 1.95 (s, 2H), 1.32 (s, 2H), 0.96 (s, 6H), 0.95 (s, 6H).

Step 2:4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile(210)

The demethylation protocol described for 208 was used.4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile(209) (0.700 g, 1.95 mmol) was treated with BBr₃ to afford 0.350 g (52%)of compound 210 as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.58 (d,J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.02.(d, J=8.4 Hz, 2H), 6.79 (d,J=8.7 Hz, 2H), 2.01 (s, 2H), 1.94 (s, 2H), 1.33 (s, 2H), 0.96 (s, 6H),0.95 (s, 6H). LCMS (ESI): m/z 344 (M−H)⁻.

Example 79 (213)

Step 1:4-[(4-Bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol(211)

The general McMurry procedure, described for 14 was employed using(4-bromophenyl)(4-hydroxyphenyl)methanone (2) (2.10 g, 7.58 mmol), and2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (1.40 g, 8.96 g). Standardwork-up followed by purification gave 2.64 g (87%) of the title compound211 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.37 (s, 1H),7.49 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H),6.70 (d, J=8.4 Hz, 2H), 2.16 (s, 2H), 2.10 (s, 2H), 1.13 (s, 6H), 1.12(s, 6H). LCMS (ESI): m/z 399 and 401 (M−H)⁻.

Step 2:1,1-Dimethylethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate(212)

The general Heck reaction procedure, described for 15 was followed.4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol(211) (0.440 g, 1.096 mmol) was reacted with 1,1-dimethylethyl2-methyl-2-propenoate in the presence of PdCl₂(PPh₃)₂ to afford thetitle compound as a mixture of Z and E isomers. The pure E-isomer (212)was isolated by HPLC as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.58(s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.05 (d, J=8.4Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 5.80 (br s, 1H), 2.30 (d, J=3.0 Hz,4H), 2.10 (s, 3H), 1.56 (s, 9H), 1.27 (s, 12H). LCMS (ESI): m/z 461(M−H)⁻.

Step 3:(2E)-3-{4-[(4-Hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoicacid (213)

The general hydrolysis protocol, described for 195 was followed. Thus,1,1-dimethylethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate(212) (0.190 g, 0.41 mmol) was treated with TFA in CH₂Cl₂ to afford0.158 g (95%) of the title compound 213 as an off-white solid. ¹H NMR(300 MHz, CD₃OD): δ 7.68 (s, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.8Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 2.83 (d, J=5.7Hz, 4H), 2.11 (s, 3H), 1.22 (s, 12H). LCMS (ESI): m/z 405 (M−H)⁻. Anal.Calcd for C₂₆H₃₀O₄, C, 76.82; H, 7.44; Found: C, 74.81; H, 7.42.

Example 80 (215)

Step 1:(1,1-Dimethylethyl-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoate(214)

The general Heck Protocol, described for 15 was followed.4-[(4-bromophenyl) (cyclooctylidene)methyl]phenol (49) (0.371 g, 1 mmol)was treated with 1,1-dimethylethyl 2-methyl-2-propenoate in the presenceof PdCl₂(PPh₃)₂ to afford 0.205 g (47%) of 214 as a mixture of E and Z(˜65:35) isomers.

Step 2:(2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoicacid (215)

The general hydrolysis procedure described for 195 was followed.(1,1-dimethylethyl(2E/2Z)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}-2-methyl-2-propenoate(214) (0.200 g, 0.46 mmol) was treated with TFA to afford 0.160 g (92%)of the title compound 215 as a mixture of E and Z (˜65:35) isomers. Thepure E isomer was isolated by HPLC to afford the title compound 214 as awhite solid. ¹H NMR (300 MHz, CD₃OD): δ 7.67 (s, 1H), 7.38 (br d, J=6.0Hz, 2H), 7.22 (br, d, J=6.6 Hz, 2H), 7.00 (br d, J=6.6 Hz, 2H), 6.72 (brd, J=6.3 Hz, 2H), 2.31 (br s, 4H), 2.10 (s, 3H), 1.70 (br s, 2H), 1.58(br s, 8H). LCMS (ESI): m/z 375 (M−H)⁻.

Example 81 (216)

Step 1:({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetonitrile(216)

The O-alkylation procedure described for 190 was followed. To stirredmixture of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (1.18 g, 4mmol), K₂CO₃ (0.691 g, 5 mmol) and acetone (50 mL) was addedbromoacetonitrile (0.418 mL, 6.0 mmol). The reaction mixture wasrefluxed for 3.5 h. Standard work-up and purification by silica gelchromatography afforded 0.175 g (13%) of compound 216 as a white solidand 0.700 g (47%) of the bis-alkylated material2,2′-[(cycloheptylidenemethanediyl)bis(benzene-4,1-diyloxy)]diacetonitrile as a white solid. IR (film):3413, 2921, 1605, 1504, 1210, 1170, 828, 729 cm−1. ¹H NMR (300 MHz,CDCl₃): δ 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4Hz, 2H), 6.76 (d, J=8.1 Hz, 2H), 5.0 (br, 1H), 4.74 (s, 2H), 2.33 (br s,4H), 1.60 (s, 8H). LCMS (ESI): m/z 332 (M−H)⁻. Anal. Calcd forC₂₂H₂₃NO₂, C, 79.25; H, 6.95; N, 4.20; Found: C, 79.14; H, 6.90; N,4.21.

Example 82 (218)

Step 1: Ethyl4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoate(217)

The O-alkylation procedure described for 190 was used. A round-bottomflask was charged with 4,4′-(cycloheptylidenemethanediyl)diphenol (189)(0.882 g, 3 Mmol), K₂CO₃ (0.518 g, 3.75 mmol) and acetone (100 mL). Tothe above mixture ethyl 4-bromobutanoate (0.644 mL, 4.5 mmol) was addedat room RT and the mixture was refluxed for 24 h. Regular work-up andpurification by column chromatography afforded 0.400 g (33%) of thetitle compound 217 as a white solid and 0.560 g (36%) of dialkylatedproduct. 0.125 g unreacted of SM was also recovered. ¹H NMR (300 MHz,CDCl₃): δ 7.06 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.17 (q, J=14.1 Hz, 6.9Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.34 (br s,4H), 2.12 (quintet, J=13.2 Hz, J₂=6.9 Hz, 2H), 1.59 (s, 8H), 1.28 (t,J=7.2 Hz, 3H). LCMS (ESI): m/z 407 (M−H)⁻.

Step 2:4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoic acid(218)

The hydrolysis conditions described for 191 were employed. Thus, ethyl4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoate(217) (0.155 g, 0.39 mmol) was dissolved in THF and EtOH (1:1, 10 mL)and then treated with 1 N NaOH (2 ml) at 70° C. for 1 h. Uponacidification, work-up, and purification afforded 0.110 g (74%) of thetitle compound 218. ¹H NMR (300 MHz, CD₃OD): δ 7.02 (d, J=8.4 Hz, 2H),6.94 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.1 Hz, 2H),4.00 (t, J=6.3 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 2.31 (br s, 4H), 2.05(quintet, J₁=13.5 Hz, J₂=6.9 Hz, 2H), 1.60 (s, 8H). LCMS (ESI): m/z 379(M−H)⁻. Anal. Calcd for C₂₄H₂₈O₄, C, 75.76; H, 7.42; Found: C, 75.81; H,7.64.

Example 83 (221)

Step 1: 4,4′-[(3,3,5,5-Tetramethylcyclohexylidene)methanediyl]diphenol(219)

The general McMurry coupling protocol, described for 14 was followed.Coupling of bis(4-hydroxyphenyl)methanone (4.28 g, 0.02 mol) and3,3,5,5-tetramethylcyclohexanone (9.26 g, 0.06 mol) under the under thestandard reaction conditions afforded 5.65 g (84%) of the title compound221 as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ 6.96 (d, J=8.4 Hz,4H), 6.70 (d, J=8.4 Hz, 4H), 1.99 (s, 4H), 0.94 (s, 12H).

Step 2:Ethyl({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate(220)

The O-alkylation procedure described for 190 was followed. To asuspension of4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219)(1.01 g, 3 mmol), K₂CO₃ (0.518 g, 3.8 mmol), and acetone (100 mL) wasadded bromoEtOAc (0.50 mL, 4.5 mmol) at RT. The reaction mixture wasrefluxed for 3 h, and filtered. The filtrate was concentrated andpurified by flask column chromatography to afford 0.35 g (28%) of thetitle compound. In addition, 0.84 g (55%) of dialkylated product and0.12 g of starting material (219) was recovered ¹H NMR (300 MHz, CDCl₃):δ 7.28 (s, 1H), 7.09 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 6.83 (d,J=8.7 Hz, 2H), 6.75(d, J=8.4 Hz, 2H), 4.70 (br s, 1H), 4.61 (s, 3H),4.29 (q, J₁=14.1 Hz, J₂=6.9 Hz, 2H), 1.98 (d, J=3.6 Hz, 4H), 1.31 (s,2H), 1.29 (t, J=4.2 Hz, 3H), 0.94 (s, 12H). LCMS (ESI): m/z 421 (M−H)⁻.

Step 3:({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)aceticacid (221)

The hydrolysis procedure described for 191 was followed. A solution ofethyl({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate(220) (0.280 g, 0.66 mmol) in THF/EtOH (1:1, 10 mL) was treated with 1 NNaOH (5 ml, excess) at 70° C. for 1 h. Acid work-up and purificationafforded 0.20 g (77%) of the title compound 221. mp 163-164° C. ¹H NMR(300 MHz, CD₃OD): δ 7.05 (d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.85(d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 4.46 (s, 2H), 2.99 (d, J=4.8Hz, 4H), 1.30 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 393 (M−H)⁻.

Example 84 (223)

Step 1: Ethyl4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoate(222)

The O-alkylation procedure described for 190 was followed. To a solutionof 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219)(1.01 g, 3 mmol), K₂CO₃ (0.518 g, 3.8 mmol), and acetone (100 mL) wasadded bromoEtOAc (0.644 mL, 4.5 mmol) at RT. The reaction mixture wasrefluxed for 18 h and filtered. The filtrate was concentrated andpurified by flash silica gel column chromatography to afford 1.08 g(40%) of the title compound 222 as an off-white foam. In addition, 0.16g of unreacted SM (219) was recovered. LCMS (ESI): m/z 449 (M−H)⁻.

Step 2:4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoicacid (223)

The hydrolysis conditions described for 191 was followed. A solution ofethyl4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoate(222) (0.760 g, 1.7 mmol) in THF/EtOH (1:1, 40 mL) was treated with 1 NNaOH (20 ml, excess) at 70° C. for 1 h. The reaction mixture was pouredinto 20% aqueous HCl (200 mL). The precipitated product was filtered anddried under reduced pressure to afford 0.68 g (95%) of compound 223 asan off-white solid. mp 203-204° C. ¹H NMR (300 MHz, CD₃OD): δ 7.05 (d,J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.70 (d,J=8.4 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.06(quintet, J₁=13.5, J₂=6.9 Hz, 2H), 2.00 (d, J=4.2 Hz, 4H), 1.31 (s, 2H),0.94 (s, 12H). LCMS (ESI): m/z 421 (M−H)⁻. Anal. Calcd for C₂₇H₃₄O₄, C,76.75; H, 8.11; Found: C, 75.63; H, 8.03.

Example 85 (224)

Step 1: 4-(Cycloheptylidene{4-[(2-hydroxyethyl)oxy]phenyl}methyl)phenol(224)

To a cold (5° C.) solution ofethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate(190) (0.200 g, 0.53 mmol) in THF (10 mL) was added 1 M solution ofLiAlH₄ (1.3 mL, 2.5 mmol). The reaction mixture was stirred at thattemperature for 0.5 h. Reaction mixture was quenched with EtOAc (5 mL)and stirred for an additional 10 min before pouring into 20% aqueous HCl(50 ml). The reaction mixture was extracted with EtOAc (3×50 mL) and thecombined organics washed with brine (1×25 ml), dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel using hexanes and EtOAc (4:1 to 3:2)as an eluent to afford 155 mg (86%) of compound 224 as a white solid. ¹HNMR (300 MHz, CD₃OD): δ 7.04 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H),6.86 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.03 (t, J=5.1 Hz, 2H),3.86 (t, J=5.1 Hz, 2H), 2.32 (d, J=4.5 Hz, 4H), 1.60 (br s, 8H). LCMS(ESI): m/z 337 (M−H)⁻.

Example 86 (226)

Step 1: Ethyl2-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate(225)

The O-alkylation procedure described for 190 was used. To a suspensionof 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (0.510 g, 1.74mmol), K₂CO₃ (0.300 g, 2.17 mmol), and acetone (75 mL) was added ethyl2-bromo-2-methylpropanoate (0.0.382 mL, 2.6 mmol) at RT. The reactionmixture was refluxed for 48 h and filtered. The filtrate wasconcentrated and purified to afford 0.320 g (45%) of the title compound225 as a white foam. In addition, 0.210 g of unreacted starting materialwas recovered. ¹H NMR (300 MHz, CD₃OD): δ 7.02 (d, J=1.8 Hz, 2H), 6.99(d, J=2.1 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.73 (d, J=1.5 Hz, 2H), 4.71(br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.30 (br d, J=3.3 Hz, 4H), 1.59 (s,6H), 1.58 (br s, 8H), 1.24 (t, J=6.9 Hz, 3H). LCMS (ESI): m/z 407(M−H)⁻.

Step 2:2-({4-[Cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoicacid (226)

The hydrolysis procedure described for 191 was employed. Ethyl2-((4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate(225) (0.150 g, 0.37 mmol) was dissolved in THF and EtOH (1:1, 6 mL) andthen treated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. Thereaction mixture was cooled and poured into 20% aqueous HCl (40 mL).Standard work-up and purification afforded 0.105 g (75%) of the titlecompound 226 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 13.06(br s, 1H), 9.26 (s, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.90 (d, J=7.8 Hz,2H), 6.72 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.1 Hz, 2H), 2.21 (br s, 4H),1.52 (br s, 8H), 1.48 (s, 6H). LCMS (ESI): m/z 379 (M−H)⁻. Anal. Calcdfor C₂₄H₂₈O₄, C, 75.76; H, 7.42; Found: C, 75.07; H, 7.52.

Example 87 (228)

Step 1: Ethyl2-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-2-methylpropanoate(227)

The O-alkylation procedure described for 190 was employed. To asuspension of4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219)(0.500 g, 1.74 mmol), K₂CO₃ (0.257 g, 1.86 mmol), and acetone (75 mL)was added ethyl 2-bromo-2-methylpropanoate (0.33 mL, 2.3 mmol) at RT.The reaction mixture was refluxed for 48 h, and filtered. The filtratewas concentrated and purified to afford 0.272 g (40%) of compound 227 asa white foam. In addition, 0.200 g of unreacted SM was recovered. ¹H NMR(300 MHz, CDCl₃): δ 7.04 (d, J=1.8 Hz, 2H), 7.01 (d, J=1.8 Hz, 2H), 6.76(d, J=1.5 Hz, 2H), 6.77 (d, J=2.7 Hz, 2H), 6.74 (d, J=2.4 Hz, 2H), 4.75(br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.96 (d, J=6.9 Hz, 4H), 1.60 (s,6H), 1.29 (s, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.934 (s, 6H), 0.92 (s, 6H).LCMS (ESI): m/z 449 (M−H)⁻.

Step 2:2-({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methylphenyl}oxy)-2-methylpropanoic acid (228)

The hydrolysis conditions described for 191 were used. A solution ofethyl2-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-2methylpropanoate (227) (0.15 g, 0.33 mmol) in THF/EtOH (1:1, 6 mL) wastreated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. Reaction mixturewas cooled and poured into 20% aqueous HCl (40 mL). Standard work-upfollowed by purification afforded 0.115 g (82%) of the title compound228 as an off-white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 13.0 (br s, 1H), 9.26 (s, 1H), 7.00 (d,J=8.7 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 6.67 (d,J=8.4 Hz, 2H), 1.89 (d, J=4.5 Hz, 4H), 1.48 (s, 6H), 1.25 9 br s, 2H),0.88 (s, 12H). LCMS (ESI): m/z 421 (M−H)⁻. Anal. Calcd for C₂₇H₃₄O₄.H₂O,C, 73.77; H, 8.19; Found: C, 74.78; H, 8.14.

Example 88 (229)

Step 1:({4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile(229)

The O-alkylation procedure described for 190 was used. To a stirredsuspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219) (0.600 g, 1.78 mmol), K₂CO₃ (0.368 g, 2.67mmol), and acetone (60 mL) was added bromoacetonitrile (0.200 mL, 2.85mmol) under a nitrogen atmosphere at RT. The reaction mixture wasrefluxed for 3 h, cooled to RT and filtered. Standard work-up followedby purification afforded 0.196 g (29%) of the title compound 229 as awhite solid along with 0.38 g (52%) of the bis-alkylated compound2,2′-[[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]bis(benzene-4,1-diyloxy)]diacetonitrile. In addition, 0.10 gof unreacted starting material (219) was recovered. ¹H NMR (300 MHz,CDCl₃): δ 7.15 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.7Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 2.00 (s, 2H), 1.98 (s,2H), 1.31 (s, 2H), 0.95 (s, 12H). LCMS (ESI): m/z 374 (M−H)⁻. Anal.Calcd for C₂₅H₂₉NO₂, C, 79.96; H, 7.78; N, 3.73; Found: C, 79.95; H,7.84; N, 3.73.

Example 89 (230)

Step 1:4-(Cycloheptylidene(4-[(2-hydroxy-1,1-dimethylethyl)oxy]phenyl}methyl)phenol(230)

The reduction procedure described for 224 was used. Ethyl2-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate(225) (0.125 g, 0.31 mmol) was treated with LiAlH₄ (0.8 mL) in THF (5mL). Standard work-up followed by purification afforded 0.086 g (76%) ofthe title compound 230 as white foam. ¹H NMR (300 MHz, DMSO-d₆): δ 9.27(s, 1H), 7.00 (d, J=7.8 Hz, 2H), 6.91 (d, J=4.5 Hz, 4H), 6.68 (d, J=8.4Hz, 2H), 4.84 (t, J=5.7 Hz, 1H), 3.34 (d, J=3.6 Hz, 2H), 2.21 (br s,4H), 1.52 (br s, 8H), 1.17 (s, 6H). LCMS (ESI): m/z 367 (M−H)⁻.

Example 90 (231)

Step 1:4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(231)

The general McMurry coupling procedure described for 14 was followed. Toa stirred suspension of zinc powder (13.0 g, 0.2 mol) in THF (400 mL)was slowly added TiCl₄ (11 mL, 0.10 mol) via a syringe at roomtemperature under a nitrogen atmosphere. The reaction mixture was heatedat reflux for 1 h. A solution of(4-fluorophenyl)(4-hydroxyphenyl)methanone (4.32 g, 0.02 mol) and3,3,5,5-tetramethylcyclohexanone (9.26 g, 0.06 mol) in THF (100 mL) wasadded to the reaction mixture. The reaction mixture was heated at refluxfor an additional 2 h. Standar work-up followed by purification gave5.450 g (80%) of compound 231 as a white solid. ¹H NMR (300 MHz, CDCl₃):δ 7.14 (d, J=5.7 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 7.04 (d, J=8.7 Hz,2H), 6.97 (dd, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.68 (s, 1H), 1.99(s, 2H), 1.96 (s, 2H), 1.31 (s, 2H), 0.95 (s, 6H), 0.94 (s, 6H).

Example 91 (232)

Step 1:4-[[4-(Hydroxymethyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(232)

To a solution of4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoicacid (26) (0.15 g, 0.41 mmol) in THF (10 mL) at 0° C. was added LAH (1 Min THF, 1.44 mL, 1.44 mmol) dropwise. The reaction mixture was stirredat 0° C. for 1 h, then heated at 50° C. for 1 h. Upon cooling in an icebath, EtOAc (5 mL) was added, and stirring continued for 10 minutes. Themixture was then acidified to pH=2 with an aqueous solution of 1 N HCl,extracted with EtOAc (2×50 mL). The combined organic extract washed withwater, brine and dried (Na₂SO₄) filtered, and the filtrate wasconcentrated to give the crude product as colorless oil. The crudeproduct was purified by flash chromatography on silica gel eluted with agradient from hexanes to 40% EtOAc:hexanes to give a white residue,which upon trituration with hot hexanes containing 1% of MeOH yielded0.12 g (83%) of compound 231 as a white solid. mp 134-135° C. ¹H NMR(400 MHz, DMSO-d₆): δ 0.85 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.86 (s,2H), 1.90 (s, 2H), 4.42 (d, J=5.7 Hz, 2H), 5.08 (t, J=5.7 Hz, 1H), 6.63(d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 7.19(d, J=8.1 Hz, 2H), 9.24 (s, 1H). LCMS (ES): m/z 349 (M−H)⁻.

Example 92 (232)

Step 1: 4-[[4-(2-Hydroxyethyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (232)

To a solution of methyl{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate(153) (0.22 g, 0.56 mmol) in THF (10 mL) at 0° C. was added LAH (1 M inTHF, 1.40 mL, 1.40 mmol) dropwise. The reaction mixture was stirred at0° C. for 1 h, EtOAc (5 mL) was added, and stirring continued for 10min. The mixture was then acidified to pH=2 with an aqueous solution of1 N HCl, extracted with EtOAc (2×50 mL). The combined organic extractwashed with water, brine and dried (Na₂SO₄) filtered, and the filtratewas concentrated to give the crude product as colorless oil. The crudeproduct was purified by flash chromatography on silica gel eluted with agradient from hexanes to 40% EtOAc:hexanes to give a white residue,which upon trituration with hot hexanes containing 1% of MeOH yielded0.185 g (91%) of the title compound 232 as a white solid. mp 159-160° C.¹H NMR (400 MHz, DMSO-d₆): δ 0.87 (s, 12H), 1.23 (s, 2H), 1.87 (s, 2H),1.89 (s, 2H), 2.65 (t, J=7.1 Hz, 2H), 3.50-3.60 (m, 2H), 4.58 (t, J=5.2Hz, 1H), 6.64 (d, J=8.2 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.00 (d, J=7.9Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 9.22 (s, 1H). LCMS (ES): m/z 365(M+H)⁺, 363 (M−H)⁻.

Example 93 (233)

Step 1:4-[[4-(3-Hydroxypropyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(233)

To a solution of methyl3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate(169) (0.176 g, 0.43 mmol) in THF (10 mL) at 0° C. was added LAH (1 M inTHF, 1.10 mL, 1.10 mmol) dropwise. The reaction mixture was stirred at0° C. for 1 h, EtOAc (5 mL) was added, and stirring continued for 10min. The mixture was then acidified to pH=2 with an aqueous solution of1 N HCl, extracted with EtOAc (2×50 mL). The combined organic extractwashed with water, brine and dried (Na₂SO₄), filtered, and the filtratewas concentrated to give the crude product as white solid. The crudeproduct was purified by flash chromatography on silica gel eluted with agradient from hexanes to 40% EtOAc:hexanes to give a white residue,which upon trituration with hot hexanes containing 1% of MeOH yielded0.15 g (92%) of compound 233 as a white solid. mp 160-161° C. ¹H NMR(400 MHz, DMSO-d₆): δ 0.85 (s, 6H), 0.86 (s, 6H), 1.23 (s, 2H),1.60-1.70 (m, 2H), 1.86 (s, 2H), 1.88 (s, 2H), 2.53 (t, J=7.8 Hz, 2H),3.35-3.40 (m, 2H), 4.42 (t, J=5.1 Hz, 1H), 6.64 (d, J=8.5 Hz, 2H), 6.89(d, J=8.5 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.1 Hz, 2H), 9.23(s, 1H). LCMS (ES): m/z 401 (M+Na)⁺, 377 (M−H)⁻.

Example 94 (234)

Step 1:4-[[4-(3-furanyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(234)

The Suzuki protocol described for (163) was employed. A round-bottomedflask was charged with4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.270 g, 0.676 mmol), PdCl₂(PPh₃)₂ (0.048 g, 0.068 mmol),3-furanylboronic acid (0.152 g, 1.35 mmol), aqueous 2 M Na₂CO₃ (1.4 mL,0.144 g, 1.35 mmol) solution, and 4:1 THF:H₂O mixture (10 mL) under anitrogen atmosphere. The reaction mixture was refluxed for 6 h. Reactionmixture was cooled to room temperature, diluted with Et₂O (10 mL) andfiltered. The filtrate was diluted with EtOAc (60 mL), washed withbrine, dried (Na₂SO₄), and concentrated under reduced pressure to affordthe crude product. The product was purified by SiO₂ chromatography usinghexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.180 g (69%) of thetitle compound (234) as white solid. mp 128° C.-129° C. ¹H NMR (400 MHz,CDCl₃): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.16 (d,J=8.0 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 6.68 (brs, 1H), 4.66 (s, 1H), 2.00 (s, 2H), 1.99 (s, 2H), 1.29 (s, 2H), 0.94 (s,12H). LCMS (ESI): m/z 385.31 (M−H)⁻.

Example 95 (235)

Step 1:4-[[4-(3,5-dimethyl-4-isoxazolyl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(235)

The Suzuki protocol described for (163) was employed. A round bottomflash was charged with4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.200 g, 0.5 mmol), PdCl₂(PPh₃)₂ (0.035 g, 0.05 mmol),(3,5-dimethyl-4-isoxazolyl)boronic acid (0.141 g, 1.0 mmol), aqueous 2 MNa₂CO₃ (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H₂O mixture (5mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 3h. Regular work-up and purification gave 0.172 g (83%) of the titlecompound (235) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.30(s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 2.38 (s, 3H), 2.20 (s, 2H), 1.91 (br s,4H), 1.25 (s, 2H), 0.892 (s, 6H), 0.88 (s, 6H). LCMS (APCI): m/z 416.10(M+H)⁺.

Example 96 (236)

Step 1:4-[[4′-(4-morpholinyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(236)

The Suzuki protocol described for (163) was employed. A round bottomflash was charged with4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.200 g, 0.5 mmol), PdCl₂(PPh₃)₂ (0.035 g, 0.05 mmol),[4-(4-morpholinyl)phenyl]boronic acid (0.270 g, 1.0 mmol), aqueous 2 MNa₂CO₃ (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H₂O mixture (5mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 3h. Regular work-up and purification gave 0.142 g (59%) of the titlecompound (236) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.27(s, 1H), 7.52 (d, J=5.2 Hz, 2H), 7.50 (d, J=4.4 Hz, 2H), 7.13 (d, J=8.4Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4Hz, 2H), 3.72 (t, J=4.4 Hz, 4H), 3.12 (t, J=4.8 Hz, 4H), 1.93 (s, 2H),1.92 (s, 2H), 1.25(s, 2H), 0.89 (s, 12H). LCMS (APCI): m/z 482.08(M+H)⁺.

Example 97 (237)

Step 1:3-fluoro-4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenylcarbonitrile(237)

The Suzuki protocol described for (163) was employed. A round-bottomedflask was charged with4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.200 g, 0.5 mmol), PdCl₂(PPh₃)₂ (0.035 g, 0.05 mmol),(4-cyano-3-fluorophenyl)boronic acid (0.165 g, 1.0 mmol), aqueous 2 MNa₂CO₃ (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H₂O (5 mL)under a nitrogen atmosphere. The reaction mixture was refluxed for 12 h.Regular work-up and purification gave 0.158 g (72%) of the titlecompound (237) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.30(s, 1H), 7.96 (dd, J₁=7.2 Hz, J₂=7.2 Hz, 1H), 7.88 and 7.85 (dd, J₁=11.2Hz, J₂=1.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 3H), 7.25 (d, J=8.4 Hz, 2H), 7.45(d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 1.93 (s, 2H), 1.92 (s, 2H),1.26 (s, 2H), 0.89 (s, 6H), 0.88 (s, 6H). LCMS (APCI): m/z 437.97(M−H)⁻.

Example 98 (238)

Step 1:4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-4-biphenylcarbonitrile (238)

The Suzuki protocol described for (163) was employed. A round-bottomedflask was charged with4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.200 g, 0.5 mmol), PdCl₂(PPh₃)₂ (0.035 g, 0.05 mmol),(4-cyanophenyl)boronic acid (0.165 g, 1.0 mmol), aqueous 2 M Na₂CO₃ (1.0mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H₂O (5 mL) under a nitrogenatmosphere. The reaction mixture was refluxed for 12 h. Regular work-upand purification gave 0.155 g (74%) of the title compound (238) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.30 (s, 1H), 7.88 (d,J=8.4 Hz, 1H), 7.87 (d, J=4.8 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.67 (d,J=8.0 Hz, 3H), 7.25 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.67 (d,J=8.4 Hz, 2H), 1.92 (br s, 4H), 1.25 (s, 2H), 0.88 (s, 12H). LCMS(APCI): m/z 419.97 (M−H)⁻.

Example 99 (239)

Step 1:4′-[cyclooctylidene(4-hydroxyphenyl)methyl]-4-biphenylcarbonitrile (239)

The Suzuki protocol described for (163) was employed. A round-bottomedflask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol(49) (0.140 g, 0.37 mmol), PdCl₂(PPh₃)₂ (0.027 g, 0.05 mmol),(4-cyanophenyl)boronic acid (0.109 g, 1.0 mmol), aqueous 2 M Na₂CO₃ (0.7mL, 0.74 mL, 0.079 g, 1.0 mmol) solution, and 4:1 THF:H₂O mixture (5 mL)under a nitrogen atmosphere. The reaction mixture was refluxed for 6 h.Upon regular work-up and purification gave 0.110 g (76%) of the titlecompound (239) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.32(s, 1H), 7.86 (d, J=4.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4Hz, 1H), 7.67 (d, J=8.00 Hz, 2H), 7.24 (d, J=8.00 Hz, 2H), 6.95 (d,J=8.4 Hz, 2H), 6.68 (d, J=8.00 Hz, 2H), 2.21 (br s, 4H), 1.61 (br s,2H), 1.49 (br m, 8H). LCMS (ESI): m/z 392.21 (M−H)⁻.

Example 100 (240)

Step 1:4-{Cycloheptylidene[4-(5-hydroxy-1-pentyn-1-yl)phenyl]methyl}phenol(240)

To a degassed solution of4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.20 g, 0.56mmol) in DMF (5 mL) were added Pd(PPh₃)₂Cl₂ (40 mg, 0.06 mmol), CuI (11mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52 mmol) and4-pentyn-1-ol (0.11 mL, 1.12 mmol). The reaction mixture was stirred at80° C. overnight, poured into saturated aqueous NH₄Cl (15 mL) and water(5 mL), extracted with ethyl acetate (3×50 mL). The combined organicphase washed with water, brine, dried over Na₂SO₄, filtered, and thefiltrate was concentrated to give the crude product as brown oil. Thecrude product was purified by chromatography on a silica gel columneluted with a gradient from hexanes to 45% EtOAc in hexanes to give alight brown solid. The solid was triturated with hot hexanes containing1% MeOH to afford 91 mg (45%) of the title compound (240) as beigesolid. mp 125-126° C. ¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (bs, 8H),1.60-1.70 (m, 2H), 2.10-2.25 (m, 4H), 2.41 (t, J=7.0 Hz, 2H), 3.40-3.50(m, 2H), 4.49 (t, J=5.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 9.27 (s, 1H).LCMS (ESI): m/z 361 (M+H)⁺, 359 (M−H)⁻.

Example 101 (241)

Step 1:4-[[4-(3-hydroxy-3-methyl-1-butyn-1-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (241)

To a degassed solution of4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)(0.25 g, 0.56 mmol) in DMF (5 mL) were added Pd(PPh₃)₂Cl₂ (40 mg, 0.06mmol), CuI (11 mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52mmol) and 2-methyl-3-butyn-2-ol (0.11 mL, 1.12 mmol). The reactionmixture was stirred at room temperature overnight, poured into saturatedaqueous NH₄Cl (15 mL) and water (5 mL), extracted with ethyl acetate(2×50 mL). The combined organic phase washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated to give thecrude product as brown oil. The crude product was purified bychromatography on a silica gel column eluted with a gradient fromhexanes to 30% EtOAc in hexanes to give a light brown solid. The solidwas triturated with hot hexanes containing 1% MeOH and 5% EtOAc inhexanes to afford 150 mg (67%) of the title compound (241) as off-whitesolid. mp 186-187° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.85 (s, 6H), 0.87(s, 6H), 1.23 (s, 2H), 1.42 (s, 6H), 1.84 (s, 2H), 1.90 (s, 2H), 5.41(s, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 9.29 (s, 1H). LCMS (ESI): m/z 401(M−H)⁻.

Example 102 (242)

Step 1:4-[[4-(4-hydroxy-1-butyn-1-yl)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(242)

To a degassed solution of4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)(0.20 g, 0.45 mmol) in DMF (5 mL) were added Pd(PPh₃)₂Cl₂ (32 mg, 0.05mmol), CuI (9 mg, 0.05 mmol), N,N-diisopropylethylamine (0.36 mL, 2.02mmol) and 3-butyn-1-ol (70 μL, 0.90 mmol). The reaction mixture wasstirred at room temperature overnight, poured into saturated aqueousNH₄Cl (15 mL) and water (5 mL), extracted with ethyl acetate (2×50 mL).The combined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asbrown oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 40% EtOAc in hexanesto give a light brown solid. The solid was triturated with hot hexanescontaining 2% MeOH and 2% CH₂Cl₂ to afford 133 mg (76%) of the titlecompound (242) as light beige solid. mp 183-184° C. ¹H NMR (400 MHz,CH₃OH-d₄): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H),1.98 (s, 2H), 2.58 (t, J=6.8 Hz, 2H), 3.70 (t, J=6.8 Hz, 2H), 6.68 (d,J=8.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.28 (d,J=8.0 Hz, 2H). LCMS (APCI): m/z 389 (M+H)⁺, 387 (M−H)⁻.

Example 103 (244)

Step 1: Methyl5-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoate(243)

4-Pentynoic acid (0.50 g, 5.0 mmol) was dissolved in DMF (15 mL). Tothis solution was added K₂CO₃ (2.76 g, 20 mmol) followed by CH₃I (0.95mL, 15 mmol). The reaction mixture was stirred at room temperatureovernight. Water was added to dissolve all solid, and the mixture wasextracted with ether (2×75 mL). The organic extracts were combined andwashed with saturated NaHCO₃, water, brine and dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude methyl4-pentynoate as colorless oil (0.29 g, 52%). To a degassed solution of4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144)(0.25 g, 0.56 mmol) in DMF (5 mL) were added Pd(PPh₃)₂Cl₂ (40 mg, 0.06mmol), CuI (11 mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52mmol) and methyl 4-pentynoate (0.15 g). The reaction mixture was stirredat room temperature overnight, poured into saturated aqueous NH₄Cl (15mL) and water (5 mL), extracted with ethyl acetate (2×50 mL). Thecombined organic phase washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product asbrown oil. The crude product was purified by chromatography on a silicagel column eluted with a gradient from hexanes to 20% EtOAc in hexanesto give a light brown solid. The solid was triturated with hot hexanescontaining 1% to afford 184 mg (76%) of the title compound (243) asoff-white solid. mp 159-160° C. ¹H NMR (400 MHz, CDCl₃): δ 0.90 (s, 6H),0.91 (s, 6H), 1.27 (s, 2H), 1.92 (s, 2H), 1.96 (s, 2H), 2.55-2.65 (m,2H), 2.65-2.75 (m, 2H), 3.71 (s, 3H), 4.58 (s, 1H), 6.72 (d, J=8.4 Hz,2H), 7.00 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.3 Hz,2H). LCMS (ESI): m/z 431 (M+H)⁺, 429 (M−H)⁻.

Step 2:5-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoicacid (244)

To a solution of methyl5-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoate(243) (0.16 g, 0.38 mmol) in a mixture of EtOH (5 mL) and THF (5 mL) wasadded an aqueous solution of 1N NaOH (6 mL). The mixture was stirred at60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with anaqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50mL). The combined organic extract washed with brine and dried overNa₂SO₄. Concentration gave a white residue, which was triturated withhot hexanes containing 1% MeOH to yield the title compound (244) aswhite solid (0.15 g, 95%), mp 233-234° C. ¹H NMR (400 MHz, CH₃OH-d₄): δ0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H), 1.98 (s, 2H),2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.94 (d,J=8.6 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H). LCMS(ESI): m/z 417 (M+H)⁺, 415 (M−H)⁻.

Example 104 (245)

Step 1:1-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}ethanone(245)

A stirred solution of4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoicacid (26) (0.138 g, 0.38 mmol) in THF (4 mL) was cooled to 0° C. in anice bath and treated rapidly with methyllithium (1.6 M in ether, 1.9 mL,3.0 mmol). After 2 h at 0° C., Me₃SiCl (1.40 mL, 10.4 mmol) was rapidlyadded while stirring continued. The ice bath was then removed and thereaction mixture was allowed to come to room temperature at which point1 N HCl (3 mL) was added, and the resulting two-phase mixture wasstirred at room temperature for 0.5 h, extracted with ether. The etherallayers were combined and washed with water, brine, dried over Na₂SO₄,filtered, and the filtrate was concentrated to give the crude product ascolorless oil. The crude product was purified by chromatography on asilica gel column eluted with a gradient from hexanes to 35% EtOAc inhexanes to give 70 mg (51%) of the title compound (245) as white solid.mp 195-196° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (s, 6H), 0.88 (s, 6H),1.25 (s, 2H), 1.86 (s, 2H), 1.92 (s, 2H), 2.52 (s, 3H), 6.66 (d, J=8.4Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.86 (d, J=8.2Hz, 2H), 9.30 (s, 1H). LCMS (ESI): m/z 361 (M−H)⁻.

Example 105 (246)

Step 1:4-[[4′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(246)

A sealed tube containing4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.20 g, 0.50 mmol), 4-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol), 2 M Na₂CO₃ (4 mL) and DME (4 mL)was heated at 160° C. for 25 min. Cooled to room temperature, themixture was extracted with EtOAc. The EtOAc extracts were combined andwashed with water, brine, dried over Na₂SO₄, filtered, and the filtratewas concentrated to give the crude product as dark brown oil. The crudeproduct was purified by chromatography on a silica gel column elutedwith a gradient from hexanes to 35% EtOAc in hexanes to give 0.16 g(75%) of the title compound (246) as pale yellow solid. mp 222-223° C.¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.92 (s, 2H),1.93 (s, 2H), 4.50 (d, J=5.7 Hz, 2H), 5.17 (t, J=5.7 Hz, 1H), 6.66 (d,J=8.4 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.35 (d,J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 9.26 (s,1H). LCMS (ESI): m/z 425 (M−H)⁻.

Example 106 (247)

Step 1:4-[[3′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(247)

A sealed tube containing4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.20 g, 0.50 mmol), 3-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol), 2 M Na₂CO₃ (4 mL) and DME (4 mL)was heated at 160° C. for 25 minutes. Cooled to room temperature, themixture was extracted with EtOAc. The EtOAc extracts were combined andwashed with water, brine, dried over Na₂SO₄, filtered, and the filtratewas concentrated to give the crude product as dark brown oil. The crudeproduct was purified by chromatography on a silica gel column elutedwith a gradient from hexanes to 30% EtOAc in hexanes to give 0.14 g(66%) of the title compound (247) as pale yellow solid. mp 197-198° C.¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.93 (s, 4H),4.52 (d, J=5.9 Hz, 2H), 5.20 (t, J=5.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H),6.95 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.5 Hz, 1H),7.37 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.52-7.58 (m, 3H), 9.27(s, 1H). LCMS (ESI): m/z 427 (M+H)⁺, 425 (M−H)⁻.

Example 107 (249)

Step 1: Methyl4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate(248)

A sealed tube containing4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14)(0.30 g, 0.75 mmol), (2-methoxycarbonylphenyl)boronic acid (0.29 g, 1.50mmol), Pd(PPh₃)₄ (87 mg, 0.08 mmol), 2 M Na₂CO₃ (4 mL) and DME (4 mL)was heated at 160° C. for 25 minutes. Cooled to room temperature, themixture was extracted with EtOAc. The EtOAc extracts were combined andwashed with water, brine, dried over Na₂SO₄, filtered, and the filtratewas concentrated to give the crude product as dark brown oil. The crudeproduct was purified by chromatography on a silica gel column elutedwith a gradient from hexanes to 20% EtOAc in hexanes to give 0.23 g(68%) of the title compound (248) as off-white solid. mp 177-178° C. ¹HNMR (400 MHz, CDCl₃): δ 0.96 (s, 6H), 0.97 (s, 6H), 1.32 (s, 2H), 2.03(s, 4H), 3.57 (s, 3H), 4.60 (s, 1H), 6.78 (d, J=8.5 Hz, 2H), 7.10 (d,J=8.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.36-7.44 (m, 2H), 7.48-7.56 (m, 1H),7.76-7.82 (m, 1H). LCMS (ESI): m/z 455 (M+H)⁺, 453 (M−H)⁻.

Step 2:4′-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylicacid (249)

To a solution of methyl4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate(248) (0.108 g, 0.24 mmol) in a mixture of EtOH (6 mL) and THF (4 mL)was added an aqueous solution of 1N NaOH (10 mL). The mixture wasstirred at 60° C. overnight. Upon cooling, the mixture was acidified topH=2 with an aqueous solution of 1 N HCl. The mixture was extracted withEtOAc (2×50 mL). The combined organic extract washed with brine anddried over Na₂SO₄. Concentration gave a white residue, which wastriturated with hot hexanes containing 1% MeOH to yield the titlecompound (249) as white solid (92.8 mg, 89%). mp 230-231° C. ¹H NMR (400MHz, DMSO-d₆): δ 0.88 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.91 (s, 4H),6.67 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H),7.23 (d, J=8.0 Hz, 2H), 7.34-7.44 (m, 2H), 7.50-7.55 (m, 1H), 7.65 (d,J=7.7 Hz, 1H), 9.27 (s, 1H), 12.72 (s, 1H). LCMS (ESI): m/z 441 (M+H)⁺,439 (M−H)⁻.

Example 108 (250)

Step 1:4-[[2′-(Hydroxymethyl)-4-biphenylyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenol(250)

To a solution of methyl4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate(248) (0.102 g, 0.23 mmol) in THF (8 mL) at 0° C. was added lithiumaluminum hydride (1 M in THF, 0.56 mL, 0.56 mmol) dropwise. The reactionmixture was stirred at 0° C. for 1 h. EtOAc (5 mL) was added, andstirring continued for 10 minutes. The mixture was then acidified topH=2 with an aqueous solution of 1 N HCl, extracted with EtOAc (2×50mL). The combined organic extract washed with water, brine and driedover Na₂SO₄, filtered, and the filtrate was concentrated to give thecrude product as light yellow oil. The crude product was purified byflash chromatography over SiO₂ eluted with a gradient from hexanes to40% EtOAc in hexanes to give 83 mg (87%) of the title compound (250) asa white solid. mp 171-172° C. ¹H NMR (400 MHz, DMSO-d₆): δ 0.88 (s, 6H),0.90 (s, 6H), 1.25(s, 2H), 1.91 (s, 2H), 1.92 (s, 2H), 4.36 (d, J=5.1Hz, 2H), 5.10 (t, J=5.3 Hz, 1H), 6.67 (d, J=8.2 Hz, 2H), 6.96 (d, J=8.2Hz, 2H), 7.12-7.23 (m, 3H), 7.24-7.36 (m, 4H), 7.53 (d, J=7.5 Hz, 1H),9.27 (s, 1H). LCMS (ESI): m/z 425 (M−H)⁻.

Biological Data

Competition Binding Assay:

Recombinant full length human ERα and ERβ protein was purchased fromPanVera (PanVera-Invitrogen Discovery Screening, Discovery Center, 501Charmany Drive, Madison, Wis. 53719, USA). Polylysine coated YttriumSilicate SPA beads (Amersham #RPNQ 0010) are resuspended in assay buffer[10 mM potassium phosphate buffer pH 7.0 containing 2 mM EDTA, 50 mMNaCl, 1 mM DTT, 2 mM CHAPs, 10% glycerol] to a concentration of 1 g/60ml. 30 ul (0.5 mg) of the SPA beads are then added to each well of aPackard OptiPlate (Packard 6005190, Packard Instruments, Meriden,Conn.). The ERα or ERβ protein is diluted to the appropriateconcentration (empirically determined for each protein prep bygenerating a protein curve using 0.5 to 10 ug total protein and 1 nM[3H] Estradiol and selecting a protein concentration that does notdeplete the radioligand) and added as 30 μl aliquots to each well. [2,4, 6, 7, 16, 17-3H(N)]-Estradiol is added as a 30 μl aliquot to give afinal assay concentration of 1 nM. To give a final volume of 100 ul,either 10 μl of a test compound solution (typically in 10% DMSO assolvent), solvent containing no test compound (to determine totalbinding, T), or solvent containing 17-b-estradiol at 100 μM (todetermine non-specific binding, NS) are finally added to the plate. Theplates are shaken vigorously for two hours then counted on a PackardTopCount using the protocol for counting tritium yttrium silicate SPAbeads. Data analysis was done by standard methods.

% Bound was Calcd for each concentration of each test compound using theequation % Bound=100*((Test−NS)/(T−NS)).

% Bound was plotted vs concentration and curve fitting was accomplishedusing non-linear regression.

At least two binding curves were generated for each compound.

The compounds of the present invention generally exhibited pIC₅₀ valuesranging from 10 μM to 1 nM.

Test compounds were employed in free or salt form.

All research complied with the principles of laboratory animal care (NIHpublication No. 85-23, revised 1985) and GlaxoSmithKline policy onanimal use.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof wherein each R² isindependently selected from OH, alkyl, or halogen; q is independentlyselected from 0, 1, or 2; X is —(CH₂)_(n)— where n is 0, 1, 2, or 3,—C(R^(g))₂—, or —O—; each of R⁶ and R⁷ are selected from H or alkyl; R⁸is —CO₂H, —(R^(h))_(t)CO₂H, or —CONR^(a)R^(b); t is 1 to 8; R^(a) is H,alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R^(b) is H, alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl; or R^(a) and R^(b) maycombine with the atoms to which they are bound to form a heteroaryl orheterocyclyl ring; R^(g) is alkyl; and each R^(h) independently is—CR^(j)R^(k)—, where each of R^(j) and R^(k) independently are selectedfrom H and alkyl.
 2. The compound of claim 1 wherein alkyl is C₁₋₈alkyl.3. The compound of claim 1 wherein q is
 0. 4. The compound of claim 1wherein each of R⁶ and R⁷ are H or C₁₋₈ alkyl.
 5. The compound of claim1 wherein X is —(CH₂)_(n)—.
 6. The compound of claim 5 wherein n is 1.7. The compound of claim 6 wherein R⁶ and R⁷ are alkyl.
 8. The compoundof claim 5 wherein n is 2 or
 3. 9. The compound of claim 8 wherein R⁶and R⁷ are hydrogen.
 10. The compound of claim 1 wherein X is —O—. 11.The compound of claim 10 wherein R⁶ and R⁷ are alkyl.
 12. The compoundof claim 1 wherein R⁸ is —CO₂H.
 13. The compound of claim 1 wherein R⁸is —CONR^(a)R^(b), and R^(a) and R^(b) combine to form a 5 or 6 memberedheterocyclyl ring optionally substituted with —CO₂H.
 14. The compoundselected from: 4-[Cycloheptylidene(4-hydroxyphenyl)methyl]benzoic acid;4-[Cyclohexylidene(4-hydroxyphenyl)methyl]benzoic acid;4-[Cyclooctylidene(4-hydroxyphenyl)methyl]benzoic acid;3-{4-[(4-Hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoic acid;4-[(4,4-Dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoicacid; 4-[Cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoicacid;4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzamide;and pharmaceutically acceptable salts thereof.
 15. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier, diluent, or excipient.